Distinct Classes of Complex Structural Variation Uncovered across Thousands of Cancer Genome Graphs.

Cancer genomes often harbor hundreds of somatic DNA rearrangement junctions, many of which cannot be easily classified into simple (e.g., deletion) or complex (e.g., chromothripsis) structural variant classes. Applying a novel genome graph computational paradigm to analyze the topology of junction copy number (JCN) across 2,778 tumor whole-genome sequences, we uncovered three novel complex rearrangement phenomena: pyrgo, rigma, and tyfonas. Pyrgo are "towers" of low-JCN duplications associated with early-replicating regions, superenhancers, and breast or ovarian cancers. Rigma comprise "chasms" of low-JCN deletions enriched in late-replicating fragile sites and gastrointestinal carcinomas. Tyfonas are "typhoons" of high-JCN junctions and fold-back inversions associated with expressed protein-coding fusions, breakend hypermutation, and acral, but not cutaneous, melanomas. Clustering of tumors according to genome graph-derived features identified subgroups associated with DNA repair defects and poor prognosis.

A genome-scale screen for synthetic drivers of T cell proliferation.

The engineering of autologous patient T cells for adoptive cell therapies has revolutionized the treatment of several types of cancer1. However, further improvements are needed to increase response and cure rates. CRISPR-based loss-of-function screens have been limited to negative regulators of T cell functions2-4 and raise safety concerns owing to the permanent modification of the genome. Here we identify positive regulators of T cell functions through overexpression of around 12,000 barcoded human open reading frames (ORFs). The top-ranked genes increased the proliferation and activation of primary human CD4+ and CD8+ T cells and their secretion of key cytokines such as interleukin-2 and interferon-γ. In addition, we developed the single-cell genomics method OverCITE-seq for high-throughput quantification of the transcriptome and surface antigens in ORF-engineered T cells. The top-ranked ORF-lymphotoxin-ß receptor (LTBR)-is typically expressed in myeloid cells but absent in lymphocytes. When overexpressed in T cells, LTBR induced profound transcriptional and epigenomic remodelling, leading to increased T cell effector functions and resistance to exhaustion in chronic stimulation settings through constitutive activation of the canonical NF-κB pathway. LTBR and other highly ranked genes improved the antigen-specific responses of chimeric antigen receptor T cells and γδ T cells, highlighting their potential for future cancer-agnostic therapies5. Our results provide several strategies for improving next-generation T cell therapies by the induction of synthetic cell programmes.

Target-dependent suppression of siRNA production modulates the levels of endogenous siRNAs in the Caenorhabditis elegans germline.

Despite the prominent role of endo-siRNAs in transposon silencing, their expression is not limited to these 'nonself' DNA elements. Transcripts of protein-coding genes ('self' DNA) in some cases also produce endo-siRNAs in yeast, plants and animals. How cells distinguish these two populations of siRNAs to prevent unwanted silencing of active genes in animals is not well understood. To address this question, we inserted various self-gene or gfp fragments into an LTR retrotransposon that produces abundant siRNAs and examined the propensity of these gene fragments to produce ectopic siRNAs in the Caenorhabditis elegans germline. We found that fragments of germline genes are generally protected from production of ectopic siRNAs. This phenomenon, which we termed 'target-directed suppression of siRNA production' (or siRNA suppression), is dependent on the germline expression of target mRNA and requires germline P-granule components. We found that siRNA suppression can also occur in naturally produced endo-siRNAs. We suggest that siRNA suppression plays an important role in regulating siRNA expression and preventing self-genes from aberrant epigenetic silencing. This article has an associated 'The people behind the papers' interview.

Preoperative Risk Factors for Adverse Events in Adults Undergoing Bowel Resection for Inflammatory Bowel Disease: 15-Year Assessment of the American College of Surgeons National Surgical Quality Improvement Program.

INTRODUCTION: Older adults with inflammatory bowel disease (IBD) are at higher risk for postoperative complications as compared to their younger counterparts; however, factors contributing to this are unknown. We assessed risk factors associated with adverse IBD-related surgical outcomes, evaluated trends in emergency surgery, and explored differential risks by age. METHODS: Using the American College of Surgeons National Surgical Quality Improvement Program database, we identified adults ≥18 years of age who underwent an IBD-related intestinal resection from 2005 to 2019. Our primary outcome included a 30-day composite of mortality, readmission, reoperation, and/or major postoperative complication. RESULTS: Overall, 49,746 intestinal resections were performed with 9,390 (18.8%) occurring among older adults with IBD. Nearly 37% of older adults experienced an adverse outcome as compared to 28.1% among younger adults with IBD ( P < 0.01). Among all adults with IBD, the presence of preoperative sepsis (adjusted odds ratio [aOR], 2.08; 95% confidence interval [CI] 1.94-2.24), malnutrition (aOR, 1.22; 95% CI 1.14-1.31), dependent functional status (aOR, 6.92; 95% CI 4.36-11.57), and requiring emergency surgery (aOR, 1.50; 95% CI 1.38-1.64) increased the odds of an adverse postoperative outcome, with similar results observed when stratifying by age. Furthermore, 8.8% of surgeries among older adults were emergent, with no change observed over time ( P = 0.16). DISCUSSION: Preoperative factors contributing to the risk of an adverse surgical outcome are similar between younger and older individuals with IBD, and include elements such as malnutrition and functional status. Incorporating these measures into surgical decision-making can reduce surgical delays in older individuals at low risk and help target interventions in those at high risk, transforming care for thousands of older adults with IBD.

FACTORS ASSOCIATED WITH DEPRESSION IN PATIENTS WITH SCHIZOPHRENIA.

The aim of this study was to analyze risk factors present in schizophrenic patients with depressive symptomatology. The sample comprised of 76 respondents diagnosed with schizophrenia. In the study, we used the Positive and Negative Syndrome Scale (PANSS) and Calgary Depression Scale for Schizophrenia. The prevalence of depression was estimated to be 30%. The mean scores on the negative subscale of the PANSS were significantly higher in patients with schizophrenia and depression compared to control group (U=3.64, p=0.00), and so were those on the General Psychopathology Scale (U=4.91, p=0.00). Socio-demographic factors were identified as important factors (p<0.05). Personal and environmental factors such as loneliness, immediate social environment, social support and isolation were statistically significantly different between the groups (p<0.05). There was a correlation of poor compliance with psycho-pharmacotherapy, increased number of hospitalizations and shorter remission period with the severity of clinical presentation (p<0.05). Since the presence of these factors is associated with depression in schizophrenia, their early detection in clinical practice is vital to ensure timely prevention of the development of depressive symptomatology.

Recurrent somatic mutations as predictors of immunotherapy response.

Immune checkpoint blockade (ICB) has transformed the treatment of metastatic cancer but is hindered by variable response rates. A key unmet need is the identification of biomarkers that predict treatment response. To address this, we analyzed six whole exome sequencing cohorts with matched disease outcomes to identify genes and pathways predictive of ICB response. To increase detection power, we focus on genes and pathways that are significantly mutated following correction for epigenetic, replication timing, and sequence-based covariates. Using this technique, we identify several genes (BCLAF1, KRAS, BRAF, and TP53) and pathways (MAPK signaling, p53 associated, and immunomodulatory) as predictors of ICB response and develop the Cancer Immunotherapy Response CLassifiEr (CIRCLE). Compared to tumor mutational burden alone, CIRCLE led to superior prediction of ICB response with a 10.5% increase in sensitivity and a 11% increase in specificity. We envision that CIRCLE and more broadly the analysis of recurrently mutated cancer genes will pave the way for better prognostic tools for cancer immunotherapy.

C. elegans Heterochromatin Factor SET-32 Plays an Essential Role in Transgenerational Establishment of Nuclear RNAi-Mediated Epigenetic Silencing.

The dynamic process by which nuclear RNAi engages a transcriptionally active target, before the repressive state is stably established, remains largely a mystery. Here, we found that the onset of exogenous dsRNA-induced nuclear RNAi in C. elegans is a transgenerational process, and it requires a putative histone methyltransferase (HMT), SET-32. By developing a CRISPR-based genetic approach, we found that silencing establishment at the endogenous targets of germline nuclear RNAi also requires SET-32. Although SET-32 and two H3K9 HMTs, MET-2 and SET-25, are dispensable for the maintenance of silencing, they do contribute to transcriptional repression in mutants that lack the germline nuclear Argonaute protein HRDE-1, suggesting a conditional role of heterochromatin in the maintenance phase. Our study indicates that (1) establishment and maintenance of siRNA-guided transcriptional repression are two distinct processes with different genetic requirements and (2) the rate-limiting step of the establishment phase is a transgenerational, chromatin-based process.

SOCIODEMOGRAPHIC AND PSYCHIATRIC CHARACTERISTICS AMONG HOMICIDE OFFENDERS IN SERBIA - THE PROVINCE OF VOJVODINA (1996-2005).

INTRODUCTION: Recent studies have shown a growing correlation between violence and mental illness, but there is a higher risk of violent crimes only in certain cases of mental disorders. This study presents sociodemographic and psychiatric characteristics of homicide offenders in Serbia, in the Province of Vojvodina in a 10-year period (1996-2005). Material and Methods~ The obtained data are based on performed forensic and psychiatric expert investigatfons of 154 homicide offenders in preceding period, considering sociodemographic data, personal history and current psychiatric status. Data were analyzed using the statistical John's Macintosh programe. RESULTS: The male offenders were in the great majority (92%) as well as a low level of education (87%). A positive history of criminal acts was found in 24% of the subjects. Minority of subjects (21%) consumed alcohol on a daily basis. At the time of committing the crimes, 57% of homicide offenders were under the influence of alcohol, and just 2% of other psychoactive substances. Among the offenders who had previously received psychiatric treatment (31.2%), the most frequent diagnosis was alcohol addiction (25%) and anxiety disorders (22.9%). During the psychiatric examination 70.8% of the subjects were diagnosed with mental disorder: personality disorders (41%), alcohol addiction (84%), neurotic disorders (65%), schizophrenic psychosis (5.2%), affective disorders (3.2%), paranoid psychosis (2.6%), organic disorders (19%), psychoactive drug addiction (13%) and mental retardation (0.6%). Emotionally unstable personality disorder was dominant among personality disorders (55.6%). Diminished mental competency was established in 77.9% of subjects at the time of the homicide, being rather sever in most of them. All those diagnosed to have a psychotic disorder were mentally incompetent. CONCLUSION: Emotionally unstable disorders were the most common among the offenders who underwent forensic evaluation. A relatively low presence of psychotic disorders imposes the need for de-stigmatization particularly of the patients suffering from major mental illnesses.

[Mother's filicide with suicide attempt].

INTRODUCTION: Filicide is the killing of a son or daughter by a parent. The paper examines interaction between stress and maternal psychopathology that led to the killing. CASE OUTLINE: After prolonged conflict with her ex-husband and father of her only child, the respondent committed filicide. Two years before committing filicide, after she had divorced the father of the child, the respondent attempted suicide and had to be hospitalized. On that occasion, she was diagnosed with depressive disorder, which was not treated after hospitalization. Having killed her daughter by cutting her throat, she tried to commit suicide in the same manner, by slitting her throat. During further observation, the respondent was found to suffer from acute psychotic disorder, depressive disorder and histrionic personality disorder. These disorders in interaction with stress do not provide us with an explanation for an unusual and psychopathological motivation analysis of killing the child. CONCLUSION: Filicide is a violent act, most frequently multifactorial in its nature. Histrionic personality disorder in mother cannot explain the filicide act. Only interactive and dynamic evaluation of this psychiatric disorder in its longitudinal, development aspects and its potentiality to enable the expression of some other psychiatric disorders, especially dissociative states, as well as the importance of prolonged and acute stress and its subjective importance for the individual can shed some more light on the mental state of the mother at the time of filicide.

Evaluation of quality of life for patients with schizophrenic and schizoaffective disorders related to the use of antipsychotic therapy.

The purpose of the study was to understand the impact of using antipsychotics in the treatment of schizophrenic and schizoaffective disorders related to the quality of life and overall social functioning of schizophrenic patients. In addition to this, the study monitored and compared the efficacy of classical, commonly used antipsychotics to that of atypical antipsychotic drugs with respect to the velocity and degree of reduction in symptoms of the primary disease. The 160 respondents who participated in this research were divided into two groups of 80. The respondents in the first group (A) were treated with atypical antipsychotics, whereas the respondents in the second group were treated with classical antipsychotics. The respondents were observed over a one-year monitoring period. Therapeutic effect of the used medicamentous therapy was monitored by means of a PANSS and CGI scales, while the velocity and degree of reduction in social functioning was monitored using the Quality of Life scale (QLS) - Heinrich-Hanlon-Carpenter-scale. The results show a remarkably improved social rehabilitation and a better quality of life, as well as higher reduction in symptoms among the respondents treated with atypical antipsychotics compared to the ones treated with classical antipsychotics.