Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer.

We conducted comprehensive integrative molecular analyses of the complete set of tumors in The Cancer Genome Atlas (TCGA), consisting of approximately 10,000 specimens and representing 33 types of cancer. We performed molecular clustering using data on chromosome-arm-level aneuploidy, DNA hypermethylation, mRNA, and miRNA expression levels and reverse-phase protein arrays, of which all, except for aneuploidy, revealed clustering primarily organized by histology, tissue type, or anatomic origin. The influence of cell type was evident in DNA-methylation-based clustering, even after excluding sites with known preexisting tissue-type-specific methylation. Integrative clustering further emphasized the dominant role of cell-of-origin patterns. Molecular similarities among histologically or anatomically related cancer types provide a basis for focused pan-cancer analyses, such as pan-gastrointestinal, pan-gynecological, pan-kidney, and pan-squamous cancers, and those related by stemness features, which in turn may inform strategies for future therapeutic development.

A national experiment reveals where a growth mindset improves achievement.

A global priority for the behavioural sciences is to develop cost-effective, scalable interventions that could improve the academic outcomes of adolescents at a population level, but no such interventions have so far been evaluated in a population-generalizable sample. Here we show that a short (less than one hour), online growth mindset intervention-which teaches that intellectual abilities can be developed-improved grades among lower-achieving students and increased overall enrolment to advanced mathematics courses in a nationally representative sample of students in secondary education in the United States. Notably, the study identified school contexts that sustained the effects of the growth mindset intervention: the intervention changed grades when peer norms aligned with the messages of the intervention. Confidence in the conclusions of this study comes from independent data collection and processing, pre-registration of analyses, and corroboration of results by a blinded Bayesian analysis.

Knockout of SLy1 decreases double-negative thymocyte proliferation and protects mice from p53-induced tumor formation.

The lymphocyte-specific adapter protein SLy1 has previously been identified as indispensable for thymocyte development and T-cell proliferation and, recently, as a cause of X-linked combined immunodeficiency in humans that recapitulates many of the abnormalities reported in SLy1KO and SLy1d/d mice. As SLy1KO NK cells show increased levels of p53, we focused our research on the interdependency of SLy1 and p53 for thymocyte development. Using RT-PCR and immunoblot analysis, we observed increased levels of p53 as well as DNA damage response proteins in SLy1KO thymocytes. To test for rescue from SLy1-induced deficiencies in thymocyte development like reduced thymocyte numbers and reduced DN to DP progression, we generated a mouse model with T cell-specific p53-deficiency on an SLy1KO background and analyzed lymphocyte populations in these mice and respective controls. Astonishingly, SLy1KO -typical deficiencies were retained, showing that SLy1 is mechanistically independent of p53. Studies of apoptosis and proliferation in SLy1KO thymocytes revealed decreased proliferation in the DN3 subpopulation as a possible reason for the decreased thymocyte number. In mice with p53-deficient T cells, we observed tumor formation leading to reduced survival, preferentially in SLy1WT mice. Thus, we suggest that a SLy1-deficiency reduces proliferation, resulting in less hematologic tumors initiated by the p53-deficiency.

Impact of higher-order dispersion on frequency-modulated combs.

Frequency-modulated (FM) combs form spontaneously in free-running semiconductor lasers and possess a vast potential for spectroscopic applications. Despite recent progress in obtaining a conclusive theoretical description, experimental FM combs often exhibit non-ideal traits, which prevents their widespread use. Here we explain this by providing a clear theoretical and experimental study of the impact of the higher-order dispersion on FM combs. We reveal that spectrally dependent dispersion is detrimental for comb performance and leads to a decreased comb bandwidth and the appearance of spectral holes. These undesirable traits can be mended by applying a radio frequency modulation of the laser bias. We show that electrical injection-locking of the laser leads to a significant increase of the comb bandwidth, a uniform-like spectral amplitudes, and the rectification of the instantaneous frequency to recover a nearly linear frequency chirp of FM combs.

Effects of hypobaric hypoxia during a simulated ultra-long-haul flight on inflammation and regeneration after muscle trauma and muscle trauma-hemorrhagic shock.

INTRODUCTION/AIMS: Because wounded warfighters or trauma victims may receive en route care to the closest medical facility via airplane transport, we investigated the effects of extended mild hypobaric hypoxia (HB), the environmental milieu of most airplanes, on inflammation and regeneration after muscle trauma or monotrauma (MT) and muscle trauma-hemorrhagic shock or polytrauma (PT). METHODS: Male C57BL/6N mice were assigned to one of six groups pertaining to injury (control/uninjured, MT, and PT) and atmospheric pressure exposure (HB and normobaric normoxia, NB). Body mass, blood and muscle leukocyte number by flow cytometry, immunohistochemistry, or both, and the muscle relative mRNA level of selected genes involved in inflammation and muscle regeneration were examined at ~1.7, 4, 8, and 14 days post trauma (dpt). At 14 dpt, the proportion of smaller- and larger-sized myofibers at the regenerating site of MT mice was determined. RESULTS: Greater body mass loss, an increased number of blood and muscle leukocytes, and differential muscle relative mRNA levels were observed in MT and PT groups compared to controls. The MT+HB or PT+HB mice demonstrated more body mass loss and altered relative mRNA level than the corresponding NB mice. Additionally, a subgroup of MT+HB mice demonstrated a greater proportion of smaller myofibers (250 to 500 µm2 ) than MT+NB mice at 14 dpt. DISCUSSION: HB exposure after muscle trauma alone may prolong regeneration. Following HB exposure, therapies that promote oxygenation may be needed during this muscle recovery.

Crush Injury and Simulated Flight Effects on Muscle Gene Expression in Female Mice.

BACKGROUND: Aeromedical evacuation provides critical care during long-distance transport of injured victims between medical facilities. Often, these victims sustain muscle trauma related to mechanical insults, such as crush. Understanding the effects of flight on injured muscle is important because the aircraft cabin represents an external environment with mild hypoxia-the cabin's altitude is 2,438 m instead of sea level. Because mild hypobaric hypoxia can alter gene expression in normal muscle and affect recovery patterns, it is beneficial to examine whether this type of hypoxia may also alter injury-related genes. OBJECTIVE: The objective of this study was to verify the hypothesis that differential gene expression occurs in response to mild hypobaric hypoxia exposure in crush-injured muscle during two early recovery (preregeneration stage) time points. METHODS: Twenty-four female mice were anesthetized, and the right gastrocnemius muscle underwent crush injury. Approximately 24 hours later, mice were exposed to normobaric normoxia or hypobaric hypoxia for 8-9 hours. After 32 or 48 hours of recovery, the mice were euthanized, and the right and left lateral gastrocnemius muscles were collected for microarray and bioinformatics analyses. RESULTS: The study hypothesis was verified. There were 353 highly upregulated, differentially expressed genes identified in the injured muscle compared to the uninjured muscle. Mid1 was upregulated in both pressure conditions regardless of injury status. There were 52 and 15 differentially expressed genes at 32 and 48 hours postinjury, respectively, in the hypobaric hypoxia-exposed, injured muscle compared to the normobaric normoxia-exposed, injured muscle. The macrophage gene Cd68 correlated with other leukocyte-related genes. DISCUSSION: These findings expand our understanding of the genetic changes that occur in muscle in response to a crush injury, including those related to the macrophage protein CD68. Nursing interventions addressing adequate functioning after crush muscle injury may need to consider the effects on Cd68 and its closely related genes. In addition, our results suggest a responsiveness of the gene Mid1 to flight-relevant hypobaric hypoxia. Changes in the expression of Mid1 may be appropriate in assessing the long-term health of flight crew members.

The emerging and diverse roles of the SLy/SASH1-protein family in health and disease-Overview of three multifunctional proteins.

Intracellular adaptor proteins are indispensable for the transduction of receptor-derived signals, as they recruit and connect essential downstream effectors. The SLy/SASH1-adaptor family comprises three highly homologous proteins, all of them sharing conserved structural motifs. The initial characterization of the first member SLy1/SASH3 (SH3 protein expressed in lymphocytes 1) in 2001 was rapidly followed by identification of SLy2/HACS1 (hematopoietic adaptor containing SH3 and SAM domains 1) and SASH1/SLy3 (SAM and SH3 domain containing 1). Based on their pronounced sequence similarity, they were subsequently classified as one family of intracellular scaffold proteins. Despite their obvious homology, the three SLy/SASH1-members fundamentally differ with regard to their expression and function in intracellular signaling. On the contrary, growing evidence clearly demonstrates an important role of all three proteins in human health and disease. In this review, we systematically summarize what is known about the SLy/SASH1-adaptors in the field of molecular cell biology and immunology. To this end, we recapitulate current research about SLy1/SASH3, SLy2/HACS1, and SASH1/SLy3, with an emphasis on their similarities and differences.

[Why do we require clinical guidelines for suicide prevention?] / Warum brauchen wir Leitlinien für Suizidprävention?

At present, there are no German guidelines regarding suicidal behaviors in adulthood despite their relevance to public health and the well-established evidence about their prevention. This paper first describes the history and background of working with guidelines. The current status of guidelines for mental illness in Germany is presented and examined for suicide-preventive content. The need for evidence-based suicide prevention and a specific guideline for suicide prevention in adults is discussed.Only via targeted suicide prevention strategies and interventions for the respective risk groups, and by paying particular attention to age and gender specificity in the outpatient as well as inpatient sector, can a high level of care for all patients be ensured. Such strategies have to pay specific attention to the interface between the individual care sectors and need to take comprehensive, easily accessible, needs-based, and affordable sustainable medical care into account. This applies to the outpatient and inpatient sectors as well as to their interfaces. Suicidality is a cross-diagnosis syndrome that occurs in different care contexts and requires complex treatment; therefore, intersectoral and multiprofessional aspects must particularly be addressed in the guideline. Scientific evidence and interdisciplinary expert consensus on the management of suicidal behavior in medical care can help reduce morbidity and mortality associated with suicidality. In August 2021, the funding of an S3 guideline "Management of Suicidality" was approved by the Federal Joint Committee.

U.S. and Finnish high school science engagement during the COVID-19 pandemic.

When the COVID-19 pandemic struck, research teams in the United States and Finland were collaborating on a study to improve adolescent academic engagement in chemistry and physics and the impact remote teaching on academic, social, and emotional learning. The ongoing "Crafting Engaging Science Environments" (CESE) intervention afforded a rare data collection opportunity. In the United States, students were surveyed at the beginning of the school year and again in May, providing information for the same 751 students from before and during the pandemic. In Finland, 203 students were surveyed during remote learning. Findings from both countries during this period of remote learning revealed that students' academic engagement was positively correlated with participation in hands-on, project-based lessons. In Finland, results showed that situational engagement occurred in only 4.7% of sampled cases. In the United States, students show that academic engagement, primarily the aspect of challenge, was enhanced during remote learning. Engagement was in turn correlated with positive socioemotional constructs related to science learning. The study's findings emphasise the importance of finding ways to ensure equitable opportunities for students to participate in project-based activities when learning remotely.

[Suicidality in older adults]. / Suizidalität im Alter.

Older people have the highest suicide risk compared to all other age groups. Expressions of no longer wanting to live are also found in a large number of older people. The reasons are usually multifactorial and sometimes go back a long way in the personal biography. Limitations resulting from physical illness, mental disorders and social problems make an important contribution. Doctors are often the contact person, even though many older people avoid direct communication in this respect. It is important to perceive and actively address indirect notes, because suicidality is also changeable in very old age. Suicide prevention includes the multimodal treatment of the physical and mental illness, including the (re)activation of resources; however, it also begins in advance, when differentiated images of old age are communicated at the societal level, social participation of older people is practised and the quality of life is maintained until the end.

Carcinogenic Helicobacter pylori Strains Selectively Dysregulate the In Vivo Gastric Proteome, Which May Be Associated with Stomach Cancer Progression.

Helicobacter pylori is the strongest risk factor for gastric cancer. Initial interactions between H. pylori and its host originate at the microbial-gastric epithelial cell interface, and contact between H. pylori and gastric epithelium activates signaling pathways that drive oncogenesis. One microbial constituent that increases gastric cancer risk is the cag pathogenicity island, which encodes a type IV secretion system that translocates the effector protein, CagA, into host cells. We previously demonstrated that infection of Mongolian gerbils with a carcinogenic cag+H. pylori strain, 7.13, recapitulates many features of H. pylori-induced gastric cancer in humans. Therefore, we sought to define gastric proteomic changes induced by H. pylori that are critical for initiation of the gastric carcinogenic cascade. Gastric cell scrapings were harvested from H. pylori-infected and uninfected gerbils for quantitative proteomic analyses using isobaric tags for relative and absolute quantitation (iTRAQ). Quantitative proteomic analysis of samples from two biological replicate experiments quantified a total of 2764 proteins, 166 of which were significantly altered in abundance by H. pylori infection. Pathway mapping identified significantly altered inflammatory and cancer-signaling pathways that included Rab/Ras signaling proteins. Consistent with the iTRAQ results, RABEP2 and G3BP2 were significantly up-regulated in vitro, ex vivo in primary human gastric monolayers, and in vivo in gerbil gastric epithelium following infection with H. pylori strain 7.13 in a cag-dependent manner. Within human stomachs, RABEP2 and G3BP2 expression in gastric epithelium increased in parallel with the severity of premalignant and malignant lesions and was significantly elevated in intestinal metaplasia and dysplasia, as well as gastric adenocarcinoma, compared with gastritis alone. These results indicate that carcinogenic strains of H. pylori induce dramatic and specific changes within the gastric proteome in vivo and that a subset of altered proteins within pathways with oncogenic potential may facilitate the progression of gastric carcinogenesis in humans.

Circadian Rhythms in Sudden Cardiac Arrest: A Review.

BACKGROUND: Sudden cardiac arrest (SCA) is a serious public health issue caused by the cessation of cardiac electrical and mechanical activity. Despite advances in pedestrian lifesaving technologies like defibrillators, the SCA mortality rate remains high, and survivors are at risk of suffering ischemic injury to various organs. Understanding the contributing factors for SCA is essential for improving morbidity and mortality. One factor capable of influencing SCA incidence and survival is the time of day at which SCA occurs. OBJECTIVES: This review focused on the effect of time of day on SCA incidence, survival rate, and survival to discharge over the past 30 years and the role of age, sex, and SCA location in modulating the timing of SCA. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews criteria guided this review. Four databases (PubMed, Cochrane Libraries, Scopus, and Cumulative Index to Nursing and Allied Health Literature) were queried for research reports or articles addressing time of day and cardiac arrest, which were subsequently screened by the authors for inclusion in this analysis. RESULTS: A total of 48 articles were included in the final analysis. This analysis showed a bimodal SCA distribution with a primary peak in the morning and a secondary peak in the afternoon; these peaks were dependent on age (older persons), sex (more frequent in males), and the location of occurrence (out-of-hospital cardiac arrest vs. in-hospital cardiac rest). Survival following SCA was lowest between midnight and 06:00 a.m. DISCUSSION: The circadian rhythm likely plays an important role in the time-of-day-dependent pattern that is evident in both the incidence of and survival following SCA. There is a renewed call for nursing research to examine or address circadian rhythm as an element in studies involving older adults and activities affecting cardiovascular or respiratory parameters.

Reliability and Learning Effect of the Glittre ADL-Test in Patients with Chronic Obstructive Pulmonary Disease.

The Glittre ADL-test (TGlittre) is a multiple-task test designed to assess functional limitation in patients with chronic obstructive pulmonary disease (COPD). Although few studies have investigated the TGlittre learning effect, the results are still conflicting. This study aimed to investigate the test-retest reliability and learning effect on TGlittre and to identify predicting factors of the learning effect in patients with COPD. Patients performed the TGlittre twice with a 30-minutes resting period between trials. TGlittre consists in measuring the time to complete five laps of a multiple ADL-like activities circuit: walking stairs, carrying a backpack, lifting objects, bending down and rising from a seated position. 124 patients with COPD were assessed [81 men; 66 ± 8 years, forced expiratory volume in one second (FEV1) 37.1 ± 15.0%pred; TGlittre 120 ± 60%pred; six-minute walking test 75.5 ± 17.4%pred]. The time spent in TGlittre presented excellent reliability (ICC = 0.96; 95%CI 0.92 - 0.98; p < 0.001; SEM 0.46 min; MDC 1.28 min) and decreased in the retest (5.24 ± 2.31 min to 4.85 ± 2.02 min; p < 0.001). Patients presented a learning effect of 6.11 ± 11.1% in TGlittre. A lower FEV1 (r2=0.10; p < 0.001) and a worse performance in the first TGlittre (r2=0.28; p < 0.001) are related to the improvement in performance of the second TGlittre. Although the TGlittre is reliable, patients improve their performance when performing the second test probably because they underestimate their functional capacity. These results should encourage professionals to assess TGlittre twice when using this test as an outcome measure.

Predictors of attendance in outpatient group treatment for women with posttraumatic stress disorder and substance use disorder.

Objective: The present study investigated predictors of treatment attendance among 226 women with posttraumatic stress disorder (PTSD) and substance use disorder (SUD). Participants received either an integrated intervention for PTSD and SUD ("Seeking Safety") or a relapse prevention training (RPT) as part of a multicenter randomized controlled trial. Method: Beta-binomial regression was conducted to investigate baseline sociodemographic, motivational, mental health and substance use predictors of session attendance. Treatment by predictor interactions were included to identify treatment-specific predictors. Results: Session attendance was predicted by employment status, drug use severity and abstinence status. Higher drug use severity and unemployment were associated with less session attendance. The effect of abstinence status was treatment-specific, with abstinent participants in RPT attending most sessions. Conclusions: Considering individual characteristics could enhance session attendance in outpatient treatment for women with PTSD and SUD. This might include matching treatment concepts to abstinence status, the identification of attendance barriers in unemployed women and more intensive treatment settings for those with severe drug use.

Substance Abuse-Related Self-Stigma in Women with Substance Use Disorder and Comorbid Posttraumatic Stress Disorder.

BACKGROUND: Self-stigma is a result of internalizing negative stereotypes by the affected person. Research on self-stigma in substance use disorders (SUD) is still scarce, especially regarding the role of childhood trauma and subsequent posttraumatic disorders. OBJECTIVES: The present study investigated the progressive model of self-stigma in women with SUD and posttraumatic stress disorder (PTSD), and the predictive value of PTSD severity and childhood trauma experiences on self-stigma. METHOD: In a cross-sectional study with 343 women with SUD and PTSD, we used the Self-Stigma in Alcohol Dependency Scale, the Childhood Trauma Questionnaire (CTQ), the PTSD Symptom Scale Interview (PSS-I), and to control for SUD severity and depression, the Addiction Severity Index Lite and the Beck Depression Inventory-II. Hierarchical regression analyses were conducted for each stage of self-stigma (aware-agree-apply-harm). RESULTS: The interrelated successive stages of self-stigma were largely confirmed. In the regression models, no significant effects of the PSS-I- and the CTQ-scores were observed at any stage of self-stigma. Agreeing with negative stereotypes was solely predicted by younger age, applying these stereotypes to oneself was higher in women with younger age, higher depression and SUD severity, and suffering from the application (harm) was only predicted by depression. CONCLUSIONS: The progressive model of self-stigma could be confirmed in women with SUD and PTSD, but PTSD severity and childhood trauma did not directly affect this process. Self-stigma appears to be related to depression in a stronger way than PTSD is related to women with SUD and PTSD.

Dynamics of Helicobacter pylori infection as a determinant of progression of gastric precancerous lesions: 16-year follow-up of an eradication trial.

OBJECTIVE: To evaluate the long-term effect of cumulative time exposed to Helicobacter pylori infection on the progression of gastric lesions. DESIGN: 795 adults with precancerous gastric lesions were randomised to receive anti-H. pylori treatment at baseline. Gastric biopsies were obtained at baseline and at 3, 6, 12 and 16 years. A total of 456 individuals attended the 16-year visit. Cumulative time of H. pylori exposure was calculated as the number of years infected during follow-up. Multivariable logistic regression models were used to estimate the risk of progression to a more advanced diagnosis (versus no change/regression) as well as gastric cancer risk by intestinal metaplasia (IM) subtype. For a more detailed analysis of progression, we also used a histopathology score assessing both severity and extension of the gastric lesions (range 1-6). The score difference between baseline and 16 years was modelled by generalised linear models. RESULTS: Individuals who were continuously infected with H. pylori for 16 years had a higher probability of progression to a more advanced diagnosis than those who cleared the infection and remained negative after baseline (p=0.001). Incomplete-type IM was associated with higher risk of progression to cancer than complete-type (OR, 11.3; 95% CI 1.4 to 91.4). The average histopathology score increased by 0.20 units/year (95% CI 0.12 to 0.28) among individuals continuously infected with H. pylori. The effect of cumulative time of infection on progression in the histopathology score was significantly higher for individuals with atrophy (without IM) than for individuals with IM (p<0.001). CONCLUSIONS: Long-term exposure to H. pylori infection was associated with progression of precancerous lesions. Individuals infected with H. pylori with these lesions may benefit from eradication, particularly those with atrophic gastritis without IM. Incomplete-type IM may be a useful marker for the identification of individuals at higher risk for cancer.

[Suicide and Suicide Prevention in Psychiatric Hospitals]. / Suizid und Suizidprävention im psychiatrischen Krankenhaus.

Suicide prevention is a central topic of psychiatry and psychotherapy. Times of changes in psychiatric inpatient treatment conceptions usually come along with an increase of psychopathology and with increasing suicide rates in psychiatric hospitals to, like seen in the seventies and eighties of last century in Germany. After a real increase of inpatient suicides during those years the number and rate of inpatient suicides decreased from about 280 of 100 000 admissions of patients in 1980 to about 50 in 2014. Young male schizophrenic patients were identified as the new high risk group despite the severely depressed patients with delusions as a traditional high risk group. Nowadays suicide prevention is part of all educational programs in psychiatry and psychotherapy.

Anaerobic Cysteine Degradation and Potential Metabolic Coordination in Salmonella enterica and Escherichia coli.

Salmonella enterica has two CyuR-activated enzymes that degrade cysteine, i.e., the aerobic CdsH and an unidentified anaerobic enzyme; Escherichia coli has only the latter. To identify the anaerobic enzyme, transcript profiling was performed for E. coli without cyuR and with overexpressed cyuR Thirty-seven genes showed at least 5-fold changes in expression, and the cyuPA (formerly yhaOM) operon showed the greatest difference. Homology suggested that CyuP and CyuA represent a cysteine transporter and an iron-sulfur-containing cysteine desulfidase, respectively. E. coli and S. enterica ΔcyuA mutants grown with cysteine generated substantially less sulfide and had lower growth yields. Oxygen affected the CyuR-dependent genes reciprocally; cyuP-lacZ expression was greater anaerobically, whereas cdsH-lacZ expression was greater aerobically. In E. coli and S. enterica, anaerobic cyuP expression required cyuR and cysteine and was induced by l-cysteine, d-cysteine, and a few sulfur-containing compounds. Loss of either CyuA or RidA, both of which contribute to cysteine degradation to pyruvate, increased cyuP-lacZ expression, which suggests that CyuA modulates intracellular cysteine concentrations. Phylogenetic analysis showed that CyuA homologs are present in obligate and facultative anaerobes, confirming an anaerobic function, and in archaeal methanogens and bacterial acetogens, suggesting an ancient origin. Our results show that CyuA is the major anaerobic cysteine-catabolizing enzyme in both E. coli and S. enterica, and it is proposed that anaerobic cysteine catabolism can contribute to coordination of sulfur assimilation and amino acid synthesis.IMPORTANCE Sulfur-containing compounds such as cysteine and sulfide are essential and reactive metabolites. Exogenous sulfur-containing compounds can alter the thiol landscape and intracellular redox reactions and are known to affect several cellular processes, including swarming motility, antibiotic sensitivity, and biofilm formation. Cysteine inhibits several enzymes of amino acid synthesis; therefore, increasing cysteine concentrations could increase the levels of the inhibited enzymes. This inhibition implies that control of intracellular cysteine levels, which is the immediate product of sulfide assimilation, can affect several pathways and coordinate metabolism. For these and other reasons, cysteine and sulfide concentrations must be controlled, and this work shows that cysteine catabolism contributes to this control.

Time Course of Inflammatory Gene Expression Following Crush Injury in Murine Skeletal Muscle.

BACKGROUND: Early inflammation and secretion of proinflammatory cytokines such as IL-1ß, IL-6, and TNF-α act as the key drivers to regulate inflammation after muscle injury. However, the effects of these key proinflammatory drivers in a noninvasive crush injury model are not well known. Understanding these effects is important for treating crush injuries that occur during natural disasters and military conflicts. PURPOSE: We studied the timed mRNA expression of IL-1ß, IL-6, and TNF-α in a noninvasive murine crush injury model to further understand their impact on proinflammatory cytokine pathways that are activated within the first 48 hours after a crush muscle injury. METHODS: A total of 25 mice were anesthetized and placed on a crush injury apparatus platform with the apparatus piston situated in direct contact with intact skin overlying the right gastrocnemius muscle. Pressure at 45 psi was applied to the piston for 30 seconds for two applications. The mice recovered for either 4, 8, 24, or 48 hours postinjury, after which we harvested the gastrocnemius muscle of both legs. Microarray, confirmatory real-time polymerase chain reaction, and immunolabeling experiments were followed by a microarray time-course analysis. RESULTS: Muscle IL-1ß mRNA rose 270-fold within 4 hours and declined rapidly at 8 hours to 196-fold, 24 hours to 96-fold, and 48 hours to 10-fold. Muscle IL-6 followed the same pattern, with a 34-fold increase at 4 hours, 29-fold increase at 8 hours, 10-fold increase at 24 hours, and 5-fold increase at 48 hours. Ingenuity Pathway Analysis of IL-6 identified activation of two major downstream signaling pathways (IL-6/Stat3 and IL-1ß/Egr1) as key activators of inflammation, regeneration, and fibrosis. DISCUSSION: Closed crush muscle injury produced robust muscle cytokine expression levels, and the microarray findings allowed us to generate our most novel hypothesis: that high expression of IL-1ß, IL-6, and TNF-α may be related to the downregulation of mitochondrial genes early after injury and triggers activation of genes in the repair and fibrosis machinery. The significance of these findings and the identified expression pathways of IL1-ß, IL-6, and TNF-α and their downstream targets in skeletal muscle will allow us to further investigate targets for improved muscle recovery and limb-saving interventions.

Human and Helicobacter pylori coevolution shapes the risk of gastric disease.

Helicobacter pylori is the principal cause of gastric cancer, the second leading cause of cancer mortality worldwide. However, H. pylori prevalence generally does not predict cancer incidence. To determine whether coevolution between host and pathogen influences disease risk, we examined the association between the severity of gastric lesions and patterns of genomic variation in matched human and H. pylori samples. Patients were recruited from two geographically distinct Colombian populations with significantly different incidences of gastric cancer, but virtually identical prevalence of H. pylori infection. All H. pylori isolates contained the genetic signatures of multiple ancestries, with an ancestral African cluster predominating in a low-risk, coastal population and a European cluster in a high-risk, mountain population. The human ancestry of the biopsied individuals also varied with geography, with mostly African ancestry in the coastal region (58%), and mostly Amerindian ancestry in the mountain region (67%). The interaction between the host and pathogen ancestries completely accounted for the difference in the severity of gastric lesions in the two regions of Colombia. In particular, African H. pylori ancestry was relatively benign in humans of African ancestry but was deleterious in individuals with substantial Amerindian ancestry. Thus, coevolution likely modulated disease risk, and the disruption of coevolved human and H. pylori genomes can explain the high incidence of gastric disease in the mountain population.