Host immune responses to enzootic and invasive pathogen lineages vary in magnitude, timing, and efficacy

Infectious diseases of wildlife continue to pose a threat to biodiversity worldwide, yet pathogens are far from monolithic in virulence. Within the same pathogen species, virulence can vary considerably depending on strain or lineage, in turn eliciting variable host responses. One pathogen that has caused extensive biodiversity loss is the amphibian-killing fungus, Batrachochytrium dendrobatidis (Bd), which is comprised of a globally widespread hypervirulent lineage (Bd-GPL), and multiple geographically restricted lineages. Whereas host immunogenomic responses to Bd-GPL have been characterized in a number of amphibian species, immunogenomic responses to geographically-restricted, enzootic Bd lineages are unknown. To examine lineage-specific host immune responses to Bd, we exposed a species of pumpkin toadlet, Brachycephalus pitanga, which is endemic to Brazil's Southern Atlantic Forest, to either the Bd-GPL or the enzootic Bd-Asia-2/Brazil (hereafter Bd-Brazil) lineage. We quantified functional immunogenomic responses over the course of infection using differential gene expression tests and coexpression network analyses. Host immune responses varied significantly with Bd lineage. Toadlet responses to Bd-Brazil were weak at early infection (26 genes differentially expressed), peaked by mid-stage infection (435 genes) and were nearly fully resolved by late-stage disease (9 genes). In contrast, responses to Bd-GPL were magnified and delayed; toadlets differentially expressed 97 genes early, 86 genes at mid-stage infection, and 728 genes by late-stage infection. Given that infection intensity did not vary between mid- and late-stage disease, this suggests that pumpkin toadlets may be at least partially tolerant to the geographically-restricted Bd-Brazil lineage. In contrast, mortality was higher in Bd-GPL-infected toadlets, suggesting that late-stage immune activation against Bd-GPL was not protective and was consistent with immune dysregulation previously observed in other species. Our results demonstrate that both the timing of immune response and the particular immune pathways activated are specific to Bd lineage. Within regions where multiple Bd lineages co-occur, and given continued global Bd movement, these differential host responses may influence not only individual disease outcome, but transmission dynamics at the population and community levels.

Chronic CNS Pathology is Associated with Abnormal Collagen Deposition and Fibrotic-like Changes

Multiple sclerosis is a chronic debilitating disease of the CNS. The relapsing remitting form of the disease is driven by CNS directed inflammation. However, in the progressive forms of the disease, inflammation has abated and the underlying pathology is less well understood. In this paper, we show that chronic lesions in progressive MS are associated with fibrotic changes, a type of pathology that has previously not thought to occur in the CNS. In an animal model of chronic MS, late stage disease contains no inflammatory infiltrates and is instead characterized by collagen deposition that is histologically similar to fibrosis. In human MS samples, chronic, but not acute lesions, are devoid of inflammatory infiltrates and instead contain significant collagen deposition. Furthermore, we demonstrate that both mouse and human astrocytes are the cellular source of collagen. These results suggest that anti-fibrotic therapy may be beneficial in the treatment of progressive MS.

Clinical and sociodemographic factors associated with late stage cervical cancer diagnosis in Botswana

Background Cervical cancer is the leading cause of female cancer mortality in Botswana with the majority of cervical cancer patients presenting with late-stage disease. The identification of factors associated with late-stage disease could reduce the cervical cancer burden. This study aims to identify potential patient level clinical and sociodemographic factors associated with a late-stage diagnosis of cervical cancer in Botswana in order to help inform future interventions at the community and individual levels to decrease cervical cancer morbidity and mortality. Results There were 984 women diagnosed with cervical cancer from January 2015 to March 2020 at two tertiary hospitals in Gaborone, Botswana. Four hundred forty women (44.7%) presented with late-stage cervical cancer, and 674 women (69.7%) were living with HIV. The mean age at diagnosis was 50.5 years. The association between late-stage (III/IV) cervical cancer at diagnosis and patient clinical and sociodemographic factors was evaluated using multivariable logistic regression with multiple imputation. Women who reported undergoing cervical cancer screening had lower odds of late-stage disease at diagnosis (OR: 0.63, 95% CI 0.47–0.84) compared to those who did not report screening. Women who had never been married had increased odds of late-stage disease at diagnosis (OR: 1.35, 95% CI 1.02–1.86) compared to women who had been married. Women with abnormal vaginal bleeding had higher odds of late-stage disease at diagnosis (OR: 2.32, 95% CI 1.70–3.16) compared to those without abnormal vaginal bleeding. HIV was not associated with a diagnosis of late-stage cervical cancer. Rural women who consulted a traditional healer had increased odds of late-stage disease at diagnosis compared to rural women who had never consulted a traditional healer (OR: 1.61, 95% CI 1.02–2.55). Conclusion Increasing education and awareness among women, regardless of their HIV status, and among providers, including traditional healers, about the benefits of cervical cancer screening and about the importance of seeking prompt medical care for abnormal vaginal bleeding, while also developing support systems for unmarried women, may help reduce cervical cancer morbidity and mortality in Botswana.

Receipt of Screening Mammography by Insured Women Diagnosed With Breast Cancer and Impact on Outcomes

Background: The purpose of this study was to determine factors associated with receipt of screening mammography by insured women before breast cancer diagnosis, and subsequent outcomes. Patients and Methods: Using claims data from commercial and federal payers linked to a regional SEER registry, we identified women diagnosed with breast cancer from 2007 to 2017 and determined receipt of screening mammography within 1 year before diagnosis. We obtained patient and tumor characteristics from the SEER registry and assigned each woman a socioeconomic deprivation score based on residential address. Multivariable logistic regression models were used to evaluate associations of patient and tumor characteristics with late-stage disease and nonreceipt of mammography. We used multivariable Cox proportional hazards models to identify predictors of subsequent mortality. Results: Among 7,047 women, 69% (n=4,853) received screening mammography before breast cancer diagnosis. Compared with women who received mammography, those with no mammography had a higher proportion of late-stage disease (34% vs 10%) and higher 5-year mortality (18% vs 6%). In multivariable modeling, late-stage disease was most associated with nonreceipt of mammography (odds ratio [OR], 4.35; 95% CI, 3.80–4.98). The Cox model indicated that nonreceipt of mammography predicted increased risk of mortality (hazard ratio [HR], 2.00; 95% CI, 1.64–2.43), independent of late-stage disease at diagnosis (HR, 5.00; 95% CI, 4.10–6.10), Charlson comorbidity index score ≥1 (HR, 2.75; 95% CI, 2.26–3.34), and negative estrogen receptor/progesterone receptor status (HR, 2.09; 95% CI, 1.67–2.61). Nonreceipt of mammography was associated with younger age (40–49 vs 50–59 years; OR, 1.69; 95% CI, 1.45–1.96) and increased socioeconomic deprivation (OR, 1.05 per decile increase; 95% CI, 1.03–1.07). Conclusions: In a cohort of insured women diagnosed with breast cancer, nonreceipt of screening mammography was significantly associated with late-stage disease and mortality, suggesting that interventions to further increase uptake of screening mammography may improve breast cancer outcomes.

The impact of COVID-19 on breast cancer stage at diagnosis.

528 Background: During the SARS-CoV-2 pandemic, routine screening mammography (SM) was stopped and diagnostic mammography (DM) was limited for several months across the United States in order to reduce patient exposure and redeploy medical personnel. We hypothesized that this delay would result in patients presenting with later-stage disease following the initial shutdown. Methods: Patients diagnosed with invasive breast cancers from 2016-2020 were identified using the Beth Israel Deaconess Medical Center Cancer Registry. Baseline patient characteristics, demographics, and clinical information were gathered and cross-referenced with our electronic medical record. Late-stage disease was defined as initial anatomic stage III-IV disease in the AJCC 8th edition staging system. The control cohort consisted of patients diagnosed from 2016-2019; patients diagnosed in 2020 were the test cohort. Chi-squared analysis was used to compare monthly distributions in stage at diagnosis between the control and test cohorts. Multivariate analysis was performed using a logistic regression model. Results: There were 1597 patients diagnosed with invasive breast cancer between 2016-2019 and 333 in 2020. Median age at diagnosis was 60 years; 99% were female, and 69.1% were white. Mammography was limited from 3/16/20-6/8/20, with 90% reduction in volume during this time. The number of screening studies performed in March, April, May, and June of 2020 were 987, 1, 4, and 721 compared to 2042, 2141, 2241, and 2142 in 2019. The volume of new diagnoses per month decreased substantially during the shutdown (see table). The proportion of patients diagnosed with late-stage disease was 6.6% in the control cohort compared to 12.6% in the 2020 test cohort (p < 0.001); 92.9% of late-stage diagnoses in 2020 occurred from June to December following the shutdown period. On multivariate analysis, year of diagnosis (2020 vs 2016-2019; OR = 4.25 95% CI 0.035-0.095, p < 0.001), lower income (<200% of the federal poverty level; OR = 2.73 95% CI 0.016-0.099, p = 0.006) and increased Charlson Comorbidity Index (OR = 12.01 95% CI 0.037-0.052, p < 0.001) were associated with later stage at diagnosis. Conclusions: Patients were more likely to be diagnosed with late-stage breast cancer following the global shutdown due to the SARS-CoV-2 pandemic. Patients with lower income and medical comorbidities were disproportionately affected. These data raise significant concerns regarding the impact of SARS-CoV-2 on cancer diagnoses and long-term outcomes, especially in vulnerable patient populations.[Table: see text]

“Ideal” approaches to Cancer drug design

In this review we present potential approaches to drug design that can facilitate cancer treatment, which so far has been difficult to achieve in the safest manner, due to the complexity of disease, presented with multiple mutations. Targeting mutant proteins is not simple as mutations are plural and sometimes unmanageable due to their large number. Many therapies have failed as a result, although we have good prognosis for the majority of cancers nowadays, it is important to understand what can be done in late stage disease.

Gastric cancer burden: Evidence from a safety-net hospital.

187 Background: Gastric cancer is a leading cause of cancer-related deaths worldwide, with more than eleven thousand estimated gastric cancer deaths expected to occur this 2020 in the United States (US). Understanding the burden and trends in gastric cancer across demographics and different locations in the US is crucial to develop effective preventive strategies. This study describes, characterizes, and identifies high risk group gastric cancer patients, who may benefit the most from preventive and management strategies. Methods: A retrospective study was conducted between 2010 to 2019 at our institution to identify patients diagnosed with gastric cancer during that period. Data on demographics, risk factors, mode of presentation, pathology, site, type, and stage of gastric cancer were obtained. Chi-square was used to compare categorical variables. Regression analysis was used to evaluate factors associated with late-stage disease and cancer type. Results: A total of 111 patients were analyzed in this study. The median age of gastric cancer patients was 52 years (range 27 to 87 years). Most of the patients were Hispanic (70.3%), non-citizens (59.5%), were uninsured (69.4%), and 67.6% were living below the federal poverty level (FPL). Also, 31.5% of the patients had a family history of cancer, had diffuse-type adenocarcinoma (61%), late-stage disease (76.6%), 52.4% of the cancers were in the distal portion of the stomach. Uninsured patients were more likely to die compared to insured patients, however, this difference was not statistically significant (64.9% vs 47.1%, p = 0.077). Age below 40, Hispanic ethnicity, being uninsured, and living below FPL were associated with higher rates of late-stage disease and diffuse-type cancer (p < 0.05). Conclusions: Our data suggest a younger age at gastric cancer diagnosis than the national average. Moreover young, and uninsured Hispanics presented with advanced gastric cancer and may represent a high-risk target population for preventive strategies.

Basic Biology of Trypanosoma brucei with reference to the development of chemotherapies

: Trypanosoma brucei are protozoan parasites that causes the lethal human disease African sleeping sickness, and the economically devastating disease of cattle, Nagana. African sleeping sickness, or Human African Trypanosomiasis (HAT) threatens 65 million people, and animal trypanosomiasis makes large areas of farmland unusable. There is no vaccine and licenced therapies against the most severe, late-stage disease are toxic, impractical and ineffective. Trypanosomes are transmitted by tsetse flies and HAT is therefore predominantly confined to the tsetse fly belt in subSaharan African. They are exclusively extracellular, and they differentiate between at least seven developmental forms that are highly adapted to host and vector niches. In the mammalian (human) host they inhabit the blood, cerebrospinal fluid (late stage disease), skin and adipose fat. In the tsetse fly vector, they travel from the tsetse midgut to the salivary glands via the ectoperitrophic space and proventriculus. Trypanosomes are evolutionarily divergent compared with most branches of eukaryotic life. Perhaps most famous for their extraordinary mechanisms of monoallelic gene expression and antigenic variation, they have also been investigated because much of their biology is either highly unconventional or extreme. Moreover, in addition to their importance as pathogens, many researchers have been attracted to the field because trypanosomes have some of the most advanced molecular genetic tools and database resources of any model system. The following will cover just some aspects of trypanosome biology and how its divergent biochemistry has been leveraged to develop drugs to treat African Sleeping sickness. It is by no means intended to be a comprehensive survey of trypanosome features. Rather, it is hoped that it will present trypanosomes as one of the most fascinating and tractable systems in which to do discovery biology.

A RAC-GEF network critical for early intestinal tumourigenesis

RAC1 activity is critical for intestinal homeostasis, and is required for hyperproliferation driven by loss of the tumour suppressor gene Apc in the murine intestine. To avoid the impact of direct targeting upon homeostasis, we reasoned that indirect targeting of RAC1 via RAC-GEFs might be effective. Transcriptional profiling of Apc deficient intestinal tissue identified Vav3 and Tiam1 as key targets. Deletion of these indicated that while TIAM1 deficiency could suppress Apc-driven hyperproliferation, it had no impact upon tumourigenesis, while VAV3 deficiency had no effect. Intriguingly, deletion of either gene resulted in upregulation of Vav2, with subsequent targeting of all three (Vav2−/−Vav3−/−Tiam1−/−), profoundly suppressing hyperproliferation, tumourigenesis and RAC1 activity, without impacting normal homeostasis. Critically, the observed RAC-GEF dependency was negated by oncogenic KRAS mutation. Together, these data demonstrate that while targeting RAC-GEF molecules may have therapeutic impact at early stages, this benefit may be lost in late stage disease.

Lung Cancer

Lung cancer is the leading cause of cancer-related deaths worldwide. Most patients are diagnosed with late-stage disease. Ninety percent of lung cancer cases can be attributed to tobacco smoking. Smoking cessation efforts have led to reductions in cancer-related deaths. Early screening can help to diagnose patients at earlier stages with improved outcomes. Lung cancer patients suffer the highest symptom burden and psychological distress above other cancers. Symptom burden is due to late-stage disease and treatment side effects. Psychological distress, anxiety, and depression are influenced by internal and external stigma. These lead to the negative impact on quality of life for lung cancer patients as well as family caregivers. Lung cancer–specific tools have been developed to assist in the screening and identification of distress, stigma, and quality-of-life metrics for lung cancer patients. Several organizations have formed to support the educational and psychological needs of lung cancer patients. Early assessment of symptom and psychological distress and integration of palliative care services can improve the quality of life of patients with lung cancer.