Immune Homeostasis: A Novel Example of Teamwork.

All living organisms must maintain homeostasis to survive, reproduce, and pass their traits on to the next generation. If homeostasis is not maintained, it can result in various diseases and ultimately lead to death. Physiologists have coined the term "homeostasis" to describe this process. With the emergence of immunology as a separate branch of medicine, the concept of immune homeostasis has been introduced. Maintaining immune homeostasis is crucial to support overall homeostasis through different immunological and non-immunological routes. Any changes in the immune system can lead to chronic inflammatory or autoimmune diseases, immunodeficiency diseases, frequent infections, and cancers. Ongoing scientific advances are exploring new avenues in immunology and immune homeostasis maintenance. This chapter introduces the concept of immune homeostasis and its maintenance through different mechanisms.

cGLRs Join Their Cousins of Pattern Recognition Receptor Family to Regulate Immune Homeostasis.

Pattern recognition receptors (PRRs) recognize danger signals such as PAMPs/MAMPs and DAMPs to initiate a protective immune response. TLRs, NLRs, CLRs, and RLRs are well-characterized PRRs of the host immune system. cGLRs have been recently identified as PRRs. In humans, the cGAS/STING signaling pathway is a part of cGLRs. cGAS recognizes cytosolic dsDNA as a PAMP or DAMP to initiate the STING-dependent immune response comprising type 1 IFN release, NF-κB activation, autophagy, and cellular senescence. The present article discusses the emergence of cGLRs as critical PRRs and how they regulate immune responses. We examined the role of cGAS/STING signaling, a well-studied cGLR system, in the activation of the immune system. The following sections discuss the role of cGAS/STING dysregulation in disease and how immune cross-talk with other PRRs maintains immune homeostasis. This understanding will lead to the design of better vaccines and immunotherapeutics for various diseases, including infections, autoimmunity, and cancers.

Obesity, bone marrow adiposity, and leukemia: Time to act.

Obesity has taken the face of a pandemic with less direct concern among the general population and scientific community. However, obesity is considered a low-grade systemic inflammation that impacts multiple organs. Chronic inflammation is also associated with different solid and blood cancers. In addition, emerging evidence demonstrates that individuals with obesity are at higher risk of developing blood cancers and have poorer clinical outcomes than individuals in a normal weight range. The bone marrow is critical for hematopoiesis, lymphopoiesis, and myelopoiesis. Therefore, it is vital to understand the mechanisms by which obesity-associated changes in BM adiposity impact leukemia development. BM adipocytes are critical to maintain homeostasis via different means, including immune regulation. However, obesity increases BM adiposity and creates a pro-inflammatory environment to upregulate clonal hematopoiesis and a leukemia-supportive environment. Obesity further alters lymphopoiesis and myelopoiesis via different mechanisms, which dysregulate myeloid and lymphoid immune cell functions mentioned in the text under different sequentially discussed sections. The altered immune cell function during obesity alters hematological malignancies and leukemia susceptibility. Therefore, obesity-induced altered BM adiposity, immune cell generation, and function impact an individual's predisposition and severity of leukemia, which should be considered a critical factor in leukemia patients.

Cancer cell-specific cGAS/STING Signaling pathway in the era of advancing cancer cell biology.

Pattern-recognition receptors (PRRs) are critical to recognizing endogenous and exogenous threats to mount a protective proinflammatory innate immune response. PRRs may be located on the outer cell membrane, cytosol, and nucleus. The cGAS/STING signaling pathway is a cytosolic PRR system. Notably, cGAS is also present in the nucleus. The cGAS-mediated recognition of cytosolic dsDNA and its cleavage into cGAMP activates STING. Furthermore, STING activation through its downstream signaling triggers different interferon-stimulating genes (ISGs), initiating the release of type 1 interferons (IFNs) and NF-κB-mediated release of proinflammatory cytokines and molecules. Activating cGAS/STING generates type 1 IFN, which may prevent cellular transformation and cancer development, growth, and metastasis. The current article delineates the impact of the cancer cell-specific cGAS/STING signaling pathway alteration in tumors and its impact on tumor growth and metastasis. This article further discusses different approaches to specifically target cGAS/STING signaling in cancer cells to inhibit tumor growth and metastasis in conjunction with existing anticancer therapies.

TIME Is Ticking for Cervical Cancer.

Cervical cancer (CC) is a major health problem among reproductive-age females and comprises a leading cause of cancer-related deaths. Human papillomavirus (HPV) is the major risk factor associated with CC incidence. However, lifestyle is also a critical factor in CC pathogenesis. Despite HPV vaccination introduction, the incidence of CC is increasing worldwide. Therefore, it becomes critical to understand the CC tumor immune microenvironment (TIME) to develop immune cell-based vaccination and immunotherapeutic approaches. The current article discusses the immune environment in the normal cervix of adult females and its role in HPV infection. The subsequent sections discuss the alteration of different immune cells comprising CC TIME and their targeting as future therapeutic approaches.

Immunometabolic reprogramming, another cancer hallmark.

Molecular carcinogenesis is a multistep process that involves acquired abnormalities in key biological processes. The complexity of cancer pathogenesis is best illustrated in the six hallmarks of the cancer: (1) the development of self-sufficient growth signals, (2) the emergence of clones that are resistant to apoptosis, (3) resistance to the antigrowth signals, (4) neo-angiogenesis, (5) the invasion of normal tissue or spread to the distant organs, and (6) limitless replicative potential. It also appears that non-resolving inflammation leads to the dysregulation of immune cell metabolism and subsequent cancer progression. The present article delineates immunometabolic reprogramming as a critical hallmark of cancer by linking chronic inflammation and immunosuppression to cancer growth and metastasis. We propose that targeting tumor immunometabolic reprogramming will lead to the design of novel immunotherapeutic approaches to cancer.

Targeting cGAS/STING signaling-mediated myeloid immune cell dysfunction in TIME.

Myeloid immune cells (MICs) are potent innate immune cells serving as first responders to invading pathogens and internal changes to cellular homeostasis. Cancer is a stage of altered cellular homeostasis that can originate in response to different pathogens, chemical carcinogens, and internal genetic/epigenetic changes. MICs express several pattern recognition receptors (PRRs) on their membranes, cytosol, and organelles, recognizing systemic, tissue, and organ-specific altered homeostasis. cGAS/STING signaling is a cytosolic PRR system for identifying cytosolic double-stranded DNA (dsDNA) in a sequence-independent but size-dependent manner. The longer the cytosolic dsDNA size, the stronger the cGAS/STING signaling activation with increased type 1 interferon (IFN) and NF-κB-dependent cytokines and chemokines' generation. The present article discusses tumor-supportive changes occurring in the tumor microenvironment (TME) or tumor immune microenvironment (TIME) MICs, specifically emphasizing cGAS/STING signaling-dependent alteration. The article further discusses utilizing MIC-specific cGAS/STING signaling modulation as critical tumor immunotherapy to alter TIME.

Disparity in Clinical Trial Participation Among Patients with Gastrointestinal Cancer.

BACKGROUND: Clinical trial participation among cancer patients remains low. We sought to examine the impact of patient- and system-level factors on clinical trial participation among gastrointestinal (GI) surgical patients. STUDY DESIGN: Adult patients with a GI cancer who underwent oncologic surgery who were enrolled in National Cancer Institute (NCI)-funded clinical trials from 2000 through 2019 were compared with trial-eligible adult patients in the National Cancer Database (NCDB) between 2004 and 2017. Multivariable logistic regression was used to identify factors associated with clinical trial participation. RESULTS: Participants from 36 NCI-funded clinical trials (n = 10,518) were compared with 2,255,730 trial-eligible nonparticipants from the NCDB. Patients aged 65 years or younger (odds ratio [OR] = 0.5, 95% CI 0.47-0.53), Medicare (OR = 0.46, 95% CI 0.43-0.49) or Medicaid (OR = 0.51, 95% CI 0.46-0.58) insurance, as well as lower levels of education (OR = 0.82, 95% CI 0.75-0.89) were associated with a lower likelihood of clinical trial enrollment. Black (OR = 0.72, 95% CI 0.67-0.78) and Asian/Pacific Islander (OR = 0.96, 95% CI 0.85-1.08) patients were less likely to participate in trials vs White patients. There were interactions between race/ethnicity and income; high-income (OR = 0.67, 95% CI 0.55-0.81) and low-income Black (OR = 0.75, 95% CI 0.66-0.87) patients were less likely, respectively, to participate than high- or low-income White individuals (p < 0.001). CONCLUSIONS: Clinical trial participation is low among adult GI cancer patients who undergo surgery in the US. Programs aimed at improving trial participation among vulnerable populations are needed to improve trial participation.

Bias Issues in Colorectal Cancer Management: A Review.

Based on census data, over one-third of the US population identifies as a racial or ethnic minority. This group of racial and ethnic minorities is more likely to develop cancer and die from it when compared with the general population of the USA. These disparities are most pronounced in the African American community. Despite overall CRC rates decreasing nationally and within certain racial and ethnic minorities in the USA, there continue to be disparities in incidence and mortality when compared with non-Hispanic Whites. The disparities in CRC incidence and mortality are related to systematic racism and bias inherent in healthcare systems and society. Disparities in CRC management will continue to exist until specific interventions are implemented in the context of each racial and ethnic group. This review's primary aim is to highlight the disparities in CRC among African Americans in the USA. For surgeons, understanding these disparities is formative to creating change and improving the quality of care, centering equity for all patients.

Disparities in Clinical Trial Participation: Multilevel Opportunities for Improvement.

Current data demonstrate ongoing inequities in surgical oncology clinical trials and understanding these disparities is vital to creating a more just and equitable health care system. Analysis of participatory patterns in cooperative group surgical oncology trials demonstrates complex relationships between race, socioeconomic status, and participation in these trials at the patient level. Further analysis reveals that provider-level implicit bias plays a significant role in access to clinical trials by minority populations. Holistic approaches to addressing disparities in clinical trial participation include creating a more robust pipeline of minority surgeon-scientists, engaging in partnerships with community advocates, and promoting public policy.

21st Century Lens on Diversity, Equity, and Inclusion in Surgery Antiracism Symposium.

Inequities in society and health care combined with underlying structural and systemic racism have demonstrated significant consequences which have resulted in a renewed focus on the current state of diversity in health care and the field of surgery. However, efforts to combat racism and increase diversity and inclusion at all levels in the field of surgery require a comprehensive review, significant commitment, and purposeful action to achieve. These actions must include increasing diversity within training program recruitment, improving retention of minority and under-represented trainees, and implementing inclusive, transparent pathways to promotion, leadership, and involvement in scientific inquiry. This symposium brings together experts in surgery, health equity and policy to address antiracism, diversity, equity, and inclusion in a comprehensive manner ranging from workforce diversity and promotion, pipeline diversity, scholarly pursuits, social and political determinants of health.

Outcomes of the First Virtual General Surgery Certifying Exam of the American Board of Surgery.

OBJECTIVE: To Study the Outcomes of the First Virtual General Surgery Certifying Exam of the American Board of Surgery. SUMMARY OF BACKGROUND DATA: The ABS General Surgery CE is normally an in-person oral examination. Due to the COVID-19 outbreak, the ABS was required to reschedule these. After 2 small pilots, the CE's October administration represented the first large-scale remote virtual exam. The purpose of this report is to compare the outcomes of this virtual and the previous in-person CEs. METHODS: CE candidates were asked to provide feedback on their experience via a survey. The passing rate was compared to the 1025 candidates who took the 2019-2020 in-person CEs. RESULTS: Of the 308 candidates who registered for the virtual CE, 306 completed the exam (99.4%) and 188 completed the survey (61.4%). The majority had a very positive experience. They rated the virtual CE as very good/excellent in security (90%), ease of exam platform (77%), audio quality (71%), video quality (69%), and overall satisfaction (86%). Notably, when asked their preference, 78% preferred the virtual exam. There were no differences in the passing rates between the virtual or in-person exams. CONCLUSIONS: The first virtual CE by the ABS was completed using available internet technology. There was high satisfaction, with the majority preferring the virtual platform. Compared to past in-person CEs, there was no difference in outcomes as measured by passing rates. These data suggest that expansion of the virtual CE may be desirable.

Landmark Series on Disparities in Surgical Oncology: Melanoma.

BACKGROUND: Although the lifetime risk of melanoma is disproportionately higher in whites, blacks have a poorer overall survival with an absolute survival difference of 25%. Significant progress has been made in melanoma treatment in the past decade; however, these successes may not be available or accessible to all segments of the population. METHODS: In this review, we highlight important studies in melanoma as well as informative retrospective studies from databases and nonmelanoma cancers where appropriate. RESULTS: There are no level I evidence-based studies on disparities in melanoma, and most likely there will never be, but the studies presented herein and clinical experience demonstrate that disparities in clinical outcomes from melanoma exists. CONCLUSIONS: By becoming aware of the disparities, we can help mitigate them by engagement, education, and corrective and empowering actions through awareness campaigns, appropriate clinical trial design, encouraging participation in clinical trials, increasing the diversity of providers, and advocacy.