Deglutarylation of glutaryl-CoA dehydrogenase by deacylating enzyme SIRT5 promotes lysine oxidation in mice.

A wide range of protein acyl modifications has been identified on enzymes across various metabolic processes; however, the impact of these modifications remains poorly understood. Protein glutarylation is a recently identified modification that can be nonenzymatically driven by glutaryl-CoA. In mammalian systems, this unique metabolite is only produced in the lysine and tryptophan oxidative pathways. To better understand the biology of protein glutarylation, we studied the relationship between enzymes within the lysine/tryptophan catabolic pathways, protein glutarylation, and regulation by the deglutarylating enzyme sirtuin 5 (SIRT5). Here, we identify glutarylation on the lysine oxidation pathway enzyme glutaryl-CoA dehydrogenase (GCDH) and show increased GCDH glutarylation when glutaryl-CoA production is stimulated by lysine catabolism. Our data reveal that glutarylation of GCDH impacts its function, ultimately decreasing lysine oxidation. We also demonstrate the ability of SIRT5 to deglutarylate GCDH, restoring its enzymatic activity. Finally, metabolomic and bioinformatic analyses indicate an expanded role for SIRT5 in regulating amino acid metabolism. Together, these data support a feedback loop model within the lysine/tryptophan oxidation pathway in which glutaryl-CoA is produced, in turn inhibiting GCDH function via glutaryl modification of GCDH lysine residues and can be relieved by SIRT5 deacylation activity.

Differential relationships between thought dimensions and momentary affect in daily life.

Commonly used to characterize mind wandering, task-unrelated thought has long been associated with negative affective outcomes. However, less is known about how other thought dimensions including intentionality and freedom of movement interact with task-unrelated thought to modulate momentary affect in everyday life. To address this, we used ecological momentary assessments to prompt participants to report their thought patterns and affective valence five times a day for seven consecutive days. Each assessment asked participants to report on their affective valence as well as several thought dimensions including their task-relatedness, intentionality and freedom of movement. We examined the latter two thought dimensions alone as well as how they interacted with the commonly examined dimension of task-relatedness with respect to their relationship to momentary affect. We replicated the well-established negative relationship between task-unrelated thought and momentary affect. Furthermore, unintentional task-unrelated thought was associated with more negative affect than intentional thought. This pattern was also observed more broadly in thoughts regardless of their task relevance. In contrast, freely moving thought was positively related to momentary affect in general. A significant interaction between task-relatedness and freedom of movement of thought revealed that the commonly reported negative relationship between task-unrelated thought and more negative affect is mitigated by freely moving thought. In summary, our findings indicate that these various thought dimensions have unique relationships with momentary affect, highlighting the importance of accounting for thought dimensions in establishing its affective and possibly other functional consequences.

Community Connectors (CCx): the strategies employed by peer to peer connectors to foster relationships with early years caregivers to improve universal early child health and development.

Blackpool is one of the most deprived Local Authority (LA) areas in England; in April 2015 the Blackpool Better Start (BBS) Partnership was allocated £45 million over 10 years from the Big Lottery Fund (BLF) as one of five 'A Better Start' initiative areas in England. The aim of the 'A Better Start' initiative is to improve outcomes for children from conception to 3 years of age. Co-designed by professionals and the community, the Community Connector (CCx) programme employs residents to directly engage caregivers of children, in seven of Blackpool's most socio-economically deprived wards. The CCx follow a socioecological framework which proposes that caregivers will be positively influenced to engage in early years activities because of connections to trained peers. Peer support models are commonly applied within targeted early years health settings (i.e., infant feeding support, literacy) yet their role to improve child outcomes at a universal level has received little attention. This paper focuses on caregiver-level evidence of the strategies employed by CCx - part of an early stage pilot study supported by Frontiers of Innovation, the Harvard Centre on the Developing Child's Research and Development platform.The study collated attendance data from Children's Centres, these are publically funded community centres providing information and activities for families with children 0-5 years of age. The study data included individual interactions between a CCx and caregiver over a 1 year period (1st April 2018 - 31st March 2019). A sampling frame was created from which a total of 22 interviews with caregivers were undertaken in early years community settings. The interview data was thematically analysed; the findings highlighted the mechanisms by which CCx served to mediate service and caregiver communication boundaries, negotiate access to spaces, and encouraged sustained engagement in longer term activities such as volunteering and training. Value was embedded by the CCx in their process of establishing and maintaining connections with caregivers through the 'everyday' conversations, their individualised approach and in demonstrating self-efficacy behaviours. Further research is required to review the impact of the CCx role in caregiver's recall of early years information, nevertheless the study provided important learning for establishing formalised CCx programmes elsewhere, and has implications for community health and early years policy and practice.

The Landscape of Videofluoroscopy in the UK: A Web-Based Survey.

Videofluoroscopy (VFS) is considered one of the gold-standard assessments of swallowing. Whilst guidelines for the application and conduct of VFS exist, their translation into clinical practice remain challenging. To build a greater understanding on how VFS clinics operate in the UK. A web-based survey was shared with speech and language therapists (SLTs) working in VFS clinics via professional networks and social media from October 2018 to January 2019. 101 responses were received. Two thirds of clinics were SLT-led, with the majority of clinics being run by two SLTs (73.6%) and a radiographer (95.5%) also known as radiologic technologists, diagnostic radiographers and medical radiation technologists. Less than 50% of radiographers had received specialist training. Around half of the clinics used a standard assessment or analysis protocol and 88.1% a rating scale. Set recipes for a range of textures were used in 53.4% of VFS clinics. Barium and water soluble contrasts were used, but only 15.8% knew the concentration of contrast used. The most commonly reported VFS pulse and frame rate was 15 per second. There was evidence of a lack of SLT knowledge regarding technical operation of VFS. Screening times varied from 0.7-10 min (median 3 min, IQR 2.5-3.5). Around 50% of respondents reported quality issues affecting analysis. In a survey of UK SLTs, translation of VFS guidance into practice was found to be limited which may impact on the quality of assessment and analysis. Collaboration with radiology, strengthening of guidelines and greater uptake of specialist training is deemed essential.

Longitudinal changes in vascular function parameters in pregnant women with chronic hypertension and association with adverse outcome: a cohort study.

OBJECTIVES: Raised vascular function measures are associated with adverse maternal and perinatal outcomes in low-risk pregnancy. This study aimed to evaluate the association between longitudinal vascular function parameters and adverse outcome in pregnant women with chronic hypertension, and to assess whether these measures vary according to baseline parameters such as black ethnicity. METHODS: This was a nested cohort study of women with chronic hypertension and a singleton pregnancy recruited to the PANDA (Pregnancy And chronic hypertension: NifeDipine vs lAbetalol as antihypertensive treatment) study at one of three UK maternity units. Women had serial pulse-wave analyses performed using the Arteriograph®, while in a sitting position, from 12 weeks' gestation onwards. Statistical analysis was performed using random-effects logistic regression models. Longitudinal vascular parameters were compared between women who developed superimposed pre-eclampsia (SPE) and those who did not, between women who delivered a small-for-gestational-age (SGA) infant (birth weight < 10th centile) and those who delivered an infant with birth weight ≥ 10th centile and between women of black ethnicity and those of non-black ethnicity. RESULTS: The cohort included 97 women with chronic hypertension and a singleton pregnancy, of whom 90% (n = 87) were randomized to antihypertensive treatment and 57% (n = 55) were of black ethnicity, with up to six (mean, three) longitudinal vascular function assessments. SPE was diagnosed in 18% (n = 17) of women and 30% (n = 29) of infants were SGA. In women who developed subsequent SPE, compared with those who did not, mean brachial systolic blood pressure (SBP) (148 mmHg vs 139 mmHg; P = 0.002), mean diastolic blood pressure (DBP) (87 mmHg vs 82 mmHg; P = 0.01), mean central aortic pressure (139 mmHg vs 128 mmHg; P = 0.001) and mean augmentation index (AIx-75) (29% vs 22%; P = 0.01) were significantly higher across gestation. In women who delivered a SGA infant compared to those who delivered an infant with birth weight ≥ 10th centile, mean brachial SBP (146 mmHg vs 138 mmHg; P = 0.001), mean DBP (86 mmHg vs 82 mmHg; P = 0.01), mean central aortic pressure (137 mmHg vs 127 mmHg; P < 0.0001) and mean pulse-wave velocity (9.1 m/s vs 8.5 m/s; P = 0.02) were higher across gestation. No longitudinal differences were found in vascular function parameters in women of black ethnicity compared with those of non-black ethnicity. CONCLUSION: There were persistent differences in vascular function parameters and brachial blood pressure throughout pregnancy in women with chronic hypertension who later developed adverse maternal or perinatal outcome. Further investigation into the possible clinical use of these findings is warranted. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Chaperoning the chaperones: Proteomic analysis of the SMN complex reveals conserved and etiologic connections to the proteostasis network.

Molecular chaperones and co-chaperones are highly conserved cellular components that perform variety of duties related to the proper three-dimensional folding of the proteome. The web of factors that carries out this essential task is called the proteostasis network (PN). Ribonucleoproteins (RNPs) represent an underexplored area in terms of the connections they make with the PN. The Survival Motor Neuron (SMN) complex is an RNP assembly chaperone and serves as a paradigm for studying how specific small nuclear (sn)RNAs are identified and paired with their client substrate proteins. SMN protein is the eponymous component of a large complex required for the biogenesis of uridine-rich small nuclear ribonucleoproteins (U-snRNPs) and localizes to distinct membraneless organelles in both the nucleus and cytoplasm of animal cells. SMN forms the oligomeric core of this complex, and missense mutations in its YG box self-interaction domain are known to cause Spinal Muscular Atrophy (SMA). The basic framework for understanding how snRNAs are assembled into U-snRNPs is known, the pathways and mechanisms used by cells to regulate their biogenesis are poorly understood. Given the importance of these processes to normal development as well as neurodegenerative disease, we set out to identify and characterize novel SMN binding partners. Here, we carried out affinity purification mass spectrometry (AP-MS) of SMN using stable fly lines exclusively expressing either wildtype or SMA-causing missense alleles. Bioinformatic analyses of the pulldown data, along with comparisons to proximity labeling studies carried out in human cells, revealed conserved connections to at least two other major chaperone systems including heat shock folding chaperones (HSPs) and histone/nucleosome assembly chaperones. Notably, we found that heat shock cognate protein Hsc70-4 and other HspA family members preferentially interacted with SMA-causing alleles of SMN. Hsc70-4 is particularly interesting because its mRNA is aberrantly sequestered by a mutant form of TDP-43 in mouse and Drosophila ALS (Amyotrophic Lateral Sclerosis) disease models. Most important, a missense allele of Hsc70-4 (HspA8 in mammals) was recently identified as a bypass suppressor of the SMA phenotype in mice. Collectively, these findings suggest that chaperone-related dysfunction lies at the etiological root of both ALS and SMA.

Developing forebrain synapses are uniquely vulnerable to sleep loss.

Sleep is an essential behavior that supports lifelong brain health and cognition. Neuronal synapses are a major target for restorative sleep function and a locus of dysfunction in response to sleep deprivation (SD). Synapse density is highly dynamic during development, becoming stabilized with maturation to adulthood, suggesting sleep exerts distinct synaptic functions between development and adulthood. Importantly, problems with sleep are common in neurodevelopmental disorders including autism spectrum disorder (ASD). Moreover, early life sleep disruption in animal models causes long lasting changes in adult behavior. Different plasticity engaged during sleep necessarily implies that developing and adult synapses will show differential vulnerability to SD. To investigate distinct sleep functions and mechanisms of vulnerability to SD across development, we systematically examined the behavioral and molecular responses to acute SD between juvenile (P21-28), adolescent (P42-49) and adult (P70-100) mice of both sexes. Compared to adults, juveniles lack robust adaptations to SD, precipitating cognitive deficits in the novel object recognition test. Subcellular fractionation, combined with proteome and phosphoproteome analysis revealed the developing synapse is profoundly vulnerable to SD, whereas adults exhibit comparative resilience. SD in juveniles, and not older mice, aberrantly drives induction of synapse potentiation, synaptogenesis, and expression of peri-neuronal nets. Our analysis further reveals the developing synapse as a convergent node between vulnerability to SD and ASD genetic risk. Together, our systematic analysis supports a distinct developmental function of sleep and reveals how sleep disruption impacts key aspects of brain development, providing mechanistic insights for ASD susceptibility.

Social Network Factors Affect Nutrition Risk in Middle-Aged and Older Adults: Results from the Canadian Longitudinal Study on Aging.

OBJECTIVES: To determine which social network, demographic, and health-indicator variables are associated with SCREEN-8 (nutrition risk) scores at two time points, three years apart, using data from the Canadian Longitudinal Study on Aging. DESIGN: A retrospective cross-sectional study. SETTING AND PARTICIPANTS: 17051 Canadians aged 45 years and older with data from baseline and first follow-up of the Canadian Longitudinal Study on Aging. MEASUREMENTS: Nutrition risk was measured using SCREEN-8. Social network factors included social network size, frequency of contact with social network members, social participation, social support, self-rated social standing, and household income. Demographic variables included age, sex assigned at birth, marital status, educational attainment, and living situation (alone or with others). Health-indicator variables included depression, disability, and self-rated general health, mental health, healthy aging, and oral health. Multivariable linear regression was used to analyze the relationship between the social network, demographic, and health-indicator variables and SCREEN-8 scores at two time points, three years apart. RESULTS: Among the social network variables, individuals with higher social participation, self-rated social standing, and social support had higher SCREEN-8 scores at baseline and follow-up. Among the demographic variables, individuals who were single or widowed, compared to married or partnered, had lower SCREEN-8 scores at both time points. For the health-indicator variables, individuals who screened negative for depression, and those with higher self-rated general health, healthy aging, and oral health had higher SCREEN-8 scores at both time points. At baseline, as age increased, SCREEN-8 scores also increased. CONCLUSION: Individuals with low social participation, low social standing, and low social support may be at increased nutrition risk and should be proactively screened by healthcare professionals. Interventions and community programs designed to increase levels of social participation and foster social support may help to reduce the prevalence of nutrition risk.

Microplastics analytics: why we should not underestimate the importance of blank controls.

Recent years have seen considerable scientific attention devoted towards documenting the presence of microplastics (MPs) in environmental samples. Due to omnipresence of environmental microplastics, however, disentangling environmental MPs from sample contamination is a challenge. Hence, the environmental (collection site and laboratory) microplastics contamination of samples during processing is a reality that we must address, in order to generate reproducible and reliable data. Here we investigated published literature and have found that around 1/5 of studies failed to use blank controls in their experiments. Additionally, only 34% of the studies used a controlled air environment for their sample processing (laminar flow, fume hood, closed laboratory, clean room, etc.). In that regard, we have also shown that preparing samples in the fume hood, leads to more microplastics > 1 µm) contamination than preparing it in the laboratory bench and the laminar flow. Although it did not completely prevent microplastics contamination, the processing of sample inside the laminar flow is the best option to reduce sample contamination during processing. Overall, we showed that blank controls are a must in microplastics sample preparation, but it is often overlooked by researchers. Supplementary Information: The online version contains supplementary material available at 10.1186/s43591-023-00065-3.

The need for environmentally realistic studies on the health effects of terrestrial microplastics.

Plastic pollution is now so widespread that microplastics are regularly detected in biological samples surveyed for their presence. Despite their pervasiveness, very little is known about the effects of microplastics on the health of terrestrial vertebrates. While emerging studies are showing that microplastics represent a potentially serious threat to animal health, data have been limited to in vivo studies on laboratory rodents that were force fed plastics. The extent to which these studies are representative of the conditions that animals and humans might actually experience in the real world is largely unknown. Here, we review 114 papers from the peer-reviewed literature in order to understand how the concentrations and types of microplastics being administered to rodents in lab studies compare to those found in terrestrial soils. From 73 in vivo lab studies, and 41 soil studies, we found that lab studies have heretofore fed rodents microplastics at concentrations that were hundreds of thousands of times greater than they would be exposed to in nature. Furthermore, health effects have been studied for only 20% of the microplastic polymers that are known to occur in soils. Plastic pollution is arguably one of the most pressing ecological and public health issues of our time, yet existing lab-based research on the health effects of terrestrial microplastics does not reflect the conditions that free-ranging vertebrates are actually experiencing. Going forward, performing more true-to-life research will be of the utmost importance to fully understand the impacts of microplastics and maintain the public's faith in the scientific process. Supplementary Information: The online version contains supplementary material available at 10.1186/s43591-023-00059-1.

RBFOX2 regulated EYA3 isoforms partner with SIX4 or ZBTB1 to control transcription during myogenesis.

Alternative splicing is a prevalent gene-regulatory mechanism, with over 95% of multi-exon human genes estimated to be alternatively spliced. Here, we describe a tissue-specific, developmentally regulated, highly conserved, and disease-associated alternative splicing event in exon 7 of the eyes absent homolog 3 (Eya3) gene. We discovered that EYA3 expression is vital to the proliferation and differentiation of myoblasts. Genome-wide transcriptomic analysis and mass spectrometry-based proteomic studies identified SIX homeobox 4 (SIX4) and zinc finger and BTB-domain containing 1 (ZBTB1), as major transcription factors that interact with EYA3 to dictate gene expression. EYA3 isoforms differentially regulate transcription, indicating that splicing aids in temporal control of gene expression during muscle cell differentiation. Finally, we identified RNA-binding fox-1 homolog 2 (RBFOX2) as the main regulator of EYA3 splicing. Together, our findings illustrate the interplay between alternative splicing and transcription during myogenesis.

Critical reflections on the concept and impact of "scaling up" in Global Mental Health.

The field of Global Mental Health (GMH) aims to address the global burden of mental illness by focusing on closing the "treatment gap" faced by many low- and middle-income countries (LMICs). To increase access to services, GMH prioritizes "scaling up" mental health services, primarily advocating for the export of Western centred and developed biomedical and psychosocial "evidence-based" approaches to the Global South. While this emphasis on scalability has resulted in the increased availability of mental health services in some LMICs, there have been few critical discussions of this strategy. This commentary critically appraises the scalability of GMH by questioning the validity and sustainability of its approach. We argue that the current approach emphasizes the development of mental health services and interventions in "silos," focusing on the treatment of mental illnesses at the exclusion of a holistic and contextualized approach to people's needs. We also question the opportunities that the current approach to GMH offers for the growth of mental health programmes of local NGOs and investigate the potential pitfalls that scalability may have on NGOs' impact and ability to innovate. This commentary argues that any "scaling up" of mental health services must place sustainability at the core of its mission by favouring the growth and development of local solutions and wider forms of support that prioritize social inclusion and long-lasting mental health recovery.

SETD2 maintains nuclear lamina stability to safeguard the genome.

Histone methyltransferases play essential roles in the organization and function of chromatin. They are also frequently mutated in human diseases including cancer1. One such often mutated methyltransferase, SETD2, associates co-transcriptionally with RNA polymerase II and catalyzes histone H3 lysine 36 trimethylation (H3K36me3) - a modification that contributes to gene transcription, splicing, and DNA repair2. While studies on SETD2 have largely focused on the consequences of its catalytic activity, the non-catalytic functions of SETD2 are largely unknown. Here we report a catalysis-independent function of SETD2 in maintaining nuclear lamina stability and genome integrity. We found that SETD2, via its intrinsically disordered N-terminus, associates with nuclear lamina proteins including lamin A/C, lamin B1, and emerin. Depletion of SETD2, or deletion of its N-terminus, resulted in widespread nuclear morphology abnormalities and genome stability defects that were reminiscent of a defective nuclear lamina. Mechanistically, the N-terminus of SETD2 facilitates the association of the mitotic kinase CDK1 with lamins, thereby promoting lamin phosphorylation and depolymerization required for nuclear envelope disassembly during mitosis. Taken together, our findings reveal an unanticipated link between the N-terminus of SETD2 and nuclear lamina organization that may underlie how SETD2 acts as a tumor suppressor.

Heavy metallic oxide nanoparticles for enhanced sensitivity in semiconducting polymer x-ray detectors.

Semiconducting polymers have previously been used as the transduction material in x-ray dosimeters, but these devices have a rather low detection sensitivity because of the low x-ray attenuation efficiency of the organic active layer. Here, we demonstrate a way to overcome this limitation through the introduction of high density nanoparticles having a high atomic number (Z) to increase the x-ray attenuation. Specifically, bismuth oxide (Bi(2)O(3)) nanoparticles (Z = 83 for Bi) are added to a poly(triarylamine) (PTAA) semiconducting polymer in the active layer of an x-ray detector. Scanning electron microscopy (SEM) reveals that the Bi(2)O(3) nanoparticles are reasonably distributed in the PTAA active layer. The reverse bias dc current-voltage characteristics for PTAA-Bi(2)O(3) diodes (with indium tin oxide (ITO) and Al contacts) have similar leakage currents to ITO/PTAA/Al diodes. Upon irradiation with 17.5 keV x-ray beams, a PTAA device containing 60 wt% Bi(2)O(3) nanoparticles demonstrates a sensitivity increase of approximately 2.5 times compared to the plain PTAA sensor. These results indicate that the addition of high-Z nanoparticles improves the performance of the dosimeters by increasing the x-ray stopping power of the active volume of the diode. Because the Bi(2)O(3) has a high density, it can be used very efficiently, achieving a high weight fraction with a low volume fraction of nanoparticles. The mechanical flexibility of the polymer is not sacrificed when the inorganic nanoparticles are incorporated.

Enacting Treaty Rights through Restoring Shoshone Ancestral Foods on the Wind River Indian Reservation.

Despite great loss in gathering and consumption of traditional foods among Indigenous communities, there is great hope for reclaiming and preserving knowledge. The Restoring Shoshone Ancestral Food Gathering (RSAFG) is a community group leading grassroots efforts on the Wind River reservation to reclaim Shoshone ancestral foods and promote food sovereignty. The story of the RSAFG promotes equitable, decolonized, and community empowered methods of reclaiming Indigenous foods by sharing three of RSAFG's acts of decolonization: 1) enacting treaty rights through gathering traditional plants, 2) demanding equitable partnerships in community-based research, and 3) sharing the story through radical authorship via layered narratives. A pesar de la gran pérdida en la recolección y el consumo de alimentos tradicionales entre las comunidades indígenas, existe una gran esperanza para recuperar y preservar el conocimiento. El Restoring Shoshone Ancestral Food Gathering (RSAFG) es un grupo comunitario que lidera los esfuerzos de base en la reserva wind river para recuperar los alimentos ancestrales shoshone y promover la soberanía alimentaria. La historia de la RSAFG promueve métodos equitativos, descolonizados y empoderados por la comunidad para recuperar los alimentos indígenas al compartir tres de los actos de descolonización de RSAFG: 1) promulgar los derechos de los tratados mediante la recolección de plantas tradicionales, 2) exigir asociaciones equitativas en la investigación basada en la comunidad, y 3) compartir la historia a través de la autoría radical a través de narrativas en capas.

Expression of passively transferred immunity against an established tumor depends on generation of cytolytic T cells in recipient. Inhibition by suppressor T cells.

The results of this study with the P815 mastocytoma confirm the results of previous studies that showed that the passive transfer of tumor-sensitized T cells from immunized donors can cause the regression of tumors growing in T cell-deficient (TXB) recipients, but not in normal recipients. The key additional finding was that the expression of adoptive immunity against tumors growing in TXB recipients is immediately preceded by a substantial production of cytolytic T cells in the recipients' draining lymph node. On the other hand, failure of adoptive immunity to be expressed against tumors growing in normal recipients was associated with a cytolytic T cell response of much lower magnitude, and a similar low magnitude response was generated in TXB recipients infused with normal spleen cells and in tumor-bearing control mice. Because the passively transferred sensitized T cells possessed no cytolytic activity of their own, the results indicate that the 6-8-d delay before adoptive immunity is expressed represents the time needed for passively transferred helper or memory T cells to give rise to a cytolytic T cell response of sufficient magnitude to destroy the recipient's tumor. In support of this interpretation was the additional finding that inhibition of the expression of adoptive immunity by the passive transfer of suppressor T cells from tumor-bearing donors was associated with a substantially reduced cytolytic T cell response in the recipient's draining lymph node. The results serve to illustrate that interpretation of the results of adoptive immunization experiments requires a knowledge of the events that take place in the adoptively immunized recipient. They support the interpretation that suppressor T cells function in this model to "down-regulate" the production of cytolytic effector T cells.

Mechanisms of anti-tumor action of Corynebacterium parvum. I. Potentiated tumor-specific immunity and its therapeutic limitations.

The anti-tumor mechanism in mice induced by a subcutaneous injection of syngeneic tumor cells admixed with Corynebacterium parvum was investigated. When mice were implanted in a hind footpad with x 2 1096) tumor cells admixed with 100 microgram C. parvum, the tumor that emerged grew progressively for about 9 d and then underwent progressive and complete regression. It was found that this C. parvum-induced regression was associated with the acquisition of a systemic, T cell-mediated mechanism of immunity to tumor-specific transplantation antigens, which enabled the host to cause the regression of an untreated test tumor growing simultaneously at a distant site. The generation of a C. parvum-potentiated anti-tumor response was dependent on the presence of tumor cells in close association with C. parvum, tumor immunogenicity, and the quantity of tumor antigen in the admixture. The anti-tumor immunity was specific for the tumor in the therapeutic admixture and could be adoptively transferred to normal recipients with Thy-1.2-positive lymphocytes, but not with serum. Complete regression of a distant test tumor by the C. parvum-tumor admixture was limited to tumors below a certain critical size.

Mechanisms of anti-tumor action of Corynebacterium parvum. II. Potentiated cytolytic T cell response and its tumor-induced suppression.

It was shown that subcutaneous implantation of P815 tumor cells admixed with Corynebacterium parvum resulted in the emergence of a tumor that grew for 9-10 d and then regressed. The onset of tumor aggression was preceded by the substantial generation in the draining lymph node and spleen of T cells capable of specifically lysing P815 target cells in vitro. The finding that the magnitude of this cytolytic response was much greater than the cytolytic response to a control tumor that grew progressively is consistent with the hypothesis that the anti-tumor action of C. parvum is based on its capacity to augment the production of T cells sensitized to tumor-specific transplantation antigens. This adjuvant action of C. parvum was revealed by additional experiments in which irradiated, nonreplicating tumor cells were substituted for living tumor cells in the admixture. The results support the conclusion that the potentiated cytolytic response to subcutaneous injection of an admixture of irradiated tumor cells and C. parvum is responsible for the ability of this admixture to cause the regression of a test tumor growing at a distant site. Finally, it was shown that the failure of the therapeutic admixture to cause the regression of distant test tumors above a certain size was associated with a failure of the admixture to cause a potentiated, anti-tumor cytolytic response. We discussed the possibility that this failure was caused by the presence of a tumor-induced state of immunosuppression.