Targeting Hypoxia Sensitizes TNBC to Cisplatin and Promotes Inhibition of Both Bulk and Cancer Stem Cells.

Development of targeted therapies for triple-negative breast cancer (TNBC) is an unmet medical need. Cisplatin has demonstrated its promising potential for the treatment of TNBC in clinical trials; however, cisplatin treatment is associated with hypoxia that, in turn, promotes cancer stem cell (CSC) enrichment and drug resistance. Therapeutic approaches to attenuate this may lead to increased cisplatin efficacy in the clinic for the treatment of TNBC. In this report we analyzed clinical datasets of TNBC and found that TNBC patients possessed higher levels of EGFR and hypoxia gene expression. A similar expression pattern was also observed in cisplatin-resistant ovarian cancer cells. We, thus, developed a new therapeutic approach to inhibit EGFR and hypoxia by combination treatment with metformin and gefitinib that sensitized TNBC cells to cisplatin and led to the inhibition of both CD44+/CD24- and ALDH+ CSCs. We demonstrated a similar inhibition efficacy on organotypic cultures of TNBC patient samples ex vivo. Since these drugs have already been used frequently in the clinic; this study illustrates a novel, clinically translatable therapeutic approach to treat patients with TNBC.

Effects of SGM Education for Undergraduate Medical Students in a Canadian Context.

Medical schools have been striving to equip students with the tools and skills needed to serve patients from the LGBTQ + community, also called the Sexual and Gender Minority (SGM) community. This study aims to assess student comfort with providing care, and faculty knowledge and preparedness in delivering SGM-centered education at our home institution. We conducted two mixed-methods surveys, one geared towards medical students across four years of study and one towards medicine faculty. Each survey collected first demographic information about participants, then used a validated tool to assess knowledge of the SGM community. The qualitative component of both surveys then consisted of a needs assessment to determine what students felt should be changed about their curriculum, and what faculty felt should change about their training to deliver this curriculum. We received 26 student responses from all 4 years of study and 35 faculty responses from a variety of medical specialties. Difference in knowledge assessment scores was not statistically significant across both cohorts. Most students felt overall comfortable providing care for sexual minority individuals, and faculty similarly felt comfortable teaching, but data showcases that perceived comfort is higher among the student cohort. We propose that students are acquiring knowledge and comfort with providing for SGM individuals from sources outside their curriculum, and that additional training of faculty is vital to ensure students not doing this independent learning do not fall through the cracks. Supplementary Information: The online version contains supplementary material available at 10.1007/s40670-023-01831-x.

Short-Term COVID-19 Pandemic-Related Endoscopy Delays Did Not Translate to Deleterious Outcomes for Patients With Inflammatory Bowel Disease: A Retrospective Cohort Study.

Background: The management of inflammatory bowel disease (IBD) requires frequent endoscopic assessment. It is unknown if measures put in place to reduce the spread of the virus SARS-CoV-2, including the delay of non-urgent patient assessments, resulted in deleterious outcomes for patients with IBD. Therefore, we aimed to determine if delays in endoscopy during the COVID-19 pandemic were associated with an increased risk of adverse IBD outcomes (emergency room, ER presentation, hospitalization, surgery, or escalation of drug therapy). Methods: A retrospective cohort study was performed in patients with IBD scheduled for outpatient endoscopies between March and August 2019 and 2020 at two tertiary care centers affiliated with Western University, London, Canada. Data pertaining to endoscopy timing, IBD drug prescription, ER attendance, hospitalization, and surgery were collected. Results: A total of 1160 endoscopies (2019, n = 718; 2020, n = 442) occurred during the study periods in 669 (2019) and 414 (2020) patients with IBD, respectively. More endoscopies were delayed in 2020 than 2019 (26.7% vs. 9.7%, respectively, P < 0.0001). Endoscopy delay was not associated with an increased risk of an adverse IBD outcome (OR = 1.23, 95%CI = 0.89-1.34, P = 0.20). Fewer adverse IBD outcomes were seen in the 2020 cohort who had endoscopy delays (n = 33/115, 28.7%) versus those without delay (n = 176/299, 58.9%, P < 0.0001). Conclusion: More endoscopy delays occurred during the COVID-19 pandemic; however, delays in general were not associated with adverse IBD outcomes, and in particular, endoscopy delays during the COVID-19 pandemic were associated with fewer deleterious IBD outcomes, suggesting that patients with IBD in need of urgent endoscopy were appropriately identified.

At the Intersection of Cardiology and Oncology: TGFß as a Clinically Translatable Therapy for TNBC Treatment and as a Major Regulator of Post-Chemotherapy Cardiomyopathy.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that accounts for the majority of breast cancer-related deaths due to the lack of specific targets for effective treatments. While there is immense focus on the development of novel therapies for TNBC treatment, a persistent and critical issue is the rate of heart failure and cardiomyopathy, which is a leading cause of mortality and morbidity amongst cancer survivors. In this review, we highlight mechanisms of post-chemotherapeutic cardiotoxicity exposure, evaluate how this is assessed clinically and highlight the transforming growth factor-beta family (TGF-ß) pathway and its significance as a mediator of cardiomyopathy. We also highlight recent findings demonstrating TGF-ß inhibition as a potent method to prevent cardiac remodeling, fibrosis and cardiomyopathy. We describe how dysregulation of the TGF-ß pathway is associated with negative patient outcomes across 32 types of cancer, including TNBC. We then highlight how TGF-ß modulation may be a potent method to target mesenchymal (CD44+/CD24-) and epithelial (ALDHhigh) cancer stem cell (CSC) populations in TNBC models. CSCs are associated with tumorigenesis, metastasis, relapse, resistance and diminished patient prognosis; however, due to plasticity and differential regulation, these populations remain difficult to target and continue to present a major barrier to successful therapy. TGF-ß inhibition represents an intersection of two fields: cardiology and oncology. Through the inhibition of cardiomyopathy, cardiac damage and heart failure may be prevented, and through CSC targeting, patient prognoses may be improved. Together, both approaches, if successfully implemented, would target the two greatest causes of cancer-related morbidity in patients and potentially lead to a breakthrough therapy.

Increased Hospitalization for IBD Patients Seen in the ER During the COVID-19 Pandemic.

Background: During the COVID-19 pandemic, the focus of many health care systems shifted in order to prioritize and allocate resources toward treating those affected by COVID-19. What this has meant for other patient populations remains unclear. We aimed to determine if there have been changes to acute care access for patients with inflammatory bowel disease (IBD) during the COVID-19 pandemic. Methods: A retrospective cohort study was performed in IBD patients seen during (March 1, 2020 to August 31, 2020) and before (March 1, 2019 to August 31, 2019) the COVID-19 pandemic. IBD-related emergency room (ER) access, hospitalization, inpatient care and follow-up and post-discharge ER access were assessed. Results: A total of 1229 participants were included. A higher proportion of patients accessed ER during the pandemic (44.6% versus 37.2%, P = 0.0097). A higher proportion of hospitalizations resulted from IBD-related ER visits during the pandemic period (41.6% versus 32.4%, OR = 1.48, 95% CI = 1.14 to 1.94, P = 0.0047), though length of stay was shorter (7.13 ± 8.95 days versus 10.11 ± 17.19 days, P = 0.015) and use of rescue infliximab was less. No change was seen in inpatient surgical intervention. Despite similar proportions of follow-up appointments post-hospital discharge (pre-pandemic, 77.9% versus pandemic, 78.3%), more ER visits occurred in the first 30 days following hospitalization for patients in the pandemic cohort (24.4% versus 11.1%, P = 0.0015). Conclusion: These data highlight the need for ER services and hospitalization amongst IBD patients during the COVID-19 pandemic. This suggests that a return to pre-pandemic IBD care infrastructure is needed to mitigate the need for acute care access.

A triple-drug nanotherapy to target breast cancer cells, cancer stem cells, and tumor vasculature.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, accounting for the majority of breast cancer-related death. Due to the lack of specific therapeutic targets, chemotherapeutic agents (e.g., paclitaxel) remain the mainstay of systemic treatment, but enrich a subpopulation of cells with tumor-initiating capacity and stem-like characteristics called cancer stem cells (CSCs); thus development of a new and effective strategy for TNBC treatment is an unmet medical need. Cancer nanomedicine has transformed the landscape of cancer drug development, allowing for a high therapeutic index. In this study, we developed a new therapy by co-encapsulating clinically approved drugs, such as paclitaxel, verteporfin, and combretastatin (CA4) in polymer-lipid hybrid nanoparticles (NPs) made of FDA-approved biomaterials. Verteporfin is a drug used in the treatment of macular degeneration and has recently been found to inhibit the Hippo/YAP (Yes-associated protein) pathway, which is known to promote the progression of breast cancer and the development of CSCs. CA4 is a vascular disrupting agent and has been tested in phase II/III of clinical trials. We found that our new three drug-NP not only effectively inhibited TNBC cell viability and cell migration, but also significantly diminished paclitaxel-induced and/or CA4-induced CSC enrichment in TNBC cells, partially through inhibiting the upregulated Hippo/YAP signaling. Combination of verteporfin and CA4 was also more effective in suppressing angiogenesis in an in vivo zebrafish model than single drug alone. The efficacy and application potential of our triple drug-NPs were further assessed by using clinically relevant patient-derived xenograft (PDX) models. Triple drug-NP effectively inhibited the viability of PDX organotypic slide cultures ex vivo and stopped the growth of PDX tumors in vivo. This study developed an approach capable of simultaneously inhibiting bulk cancer cells, CSCs, and angiogenesis.

Predictive models for cardiovascular and kidney outcomes in patients with type 2 diabetes: systematic review and meta-analyses.

OBJECTIVE: To inform a clinical practice guideline (BMJ Rapid Recommendations) considering sodium glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists for treatment of adults with type 2 diabetes, we summarised the available evidence regarding the performance of validated risk models on cardiovascular and kidney outcomes in these patients. METHODS: We systematically searched bibliographic databases in January 2020 to identify observational studies evaluating risk models for all-cause and cardiovascular mortality, heart failure (HF) hospitalisations, end-stage kidney disease (ESKD), myocardial infarction (MI) and ischaemic stroke in ambulatory adults with type 2 diabetes. Using a random effects model, we pooled discrimination measures for each model and outcome, separately, and descriptively summarised calibration plots, when available. We used the Prediction Model Risk of Bias Assessment Tool to assess risk of bias of each included study and the Grading of Recommendations, Assessment, Development, and Evaluation approach to evaluate our certainty in the evidence. RESULTS: Of 22 589 publications identified, 15 observational studies reporting on seven risk models proved eligible. Among the seven models with >1 validation cohort, the Risk Equations for Complications of Type 2 Diabetes (RECODe) had the best calibration in primary studies and the highest pooled discrimination measures for the following outcomes: all-cause mortality (C-statistics 0.75, 95% CI 0.70 to 0.80; high certainty), cardiovascular mortality (0.79, 95% CI 0.75 to 0.84; low certainty), ESKD (0.73, 95% CI 0.52 to 0.94; low certainty), MI (0.72, 95% CI 0.69 to 0.74; moderate certainty) and stroke (0.71, 95% CI 0.68 to 0.74; moderate certainty). This model does not, however, predict risk of HF hospitalisations. CONCLUSION: Of available risk models, RECODe proved to have satisfactory calibration in primary validation studies and acceptable discrimination superior to other models, though with high risk of bias in most primary studies. TRIAL REGISTRATION NUMBER: CRD42020168351.

Co-targeting Bulk Tumor and CSCs in Clinically Translatable TNBC Patient-Derived Xenografts via Combination Nanotherapy.

Triple-negative breast cancer (TNBC) accounts disproportionally for the majority of breast cancer-related deaths throughout the world. This is largely attributed to lack of a specific therapy capable of targeting both bulk tumor mass and cancer stem cells (CSC), as well as appropriate animal models to accurately evaluate treatment efficacy for clinical translation. Thus, development of effective and clinically translatable targeted therapies for TNBC is an unmet medical need. We developed a hybrid nanoparticles-based co-delivery platform containing both paclitaxel and verteporfin (PV-NP) to target TNBC patient-derived xenograft (PDX) tumor and CSCs. MRI and IVIS imaging were performed on mice containing PDX tumors to assess tumor vascularity and accumulation of NPs. NF-κB, Wnt, and YAP activities were measured by reporter assays. Mice bearing TNBC PDX tumor were treated with PV-NPs and controls, and tumors progression and CSC subpopulations were analyzed. MRI imaging indicated high vascularization of PDX tumors. IVIS imaging showed accumulation of NPs in PDX tumors. In comparison with control-NPs and free-drug combination, PV-NPs significantly retarded tumor growth of TNBC PDX. PV-NPs simultaneously repressed NF-κB, Wnt, and YAP that have been shown to be crucial for cancer growth, CSC development, and tumorigenesis. In conclusion, NPs containing two clinically used drugs concurrently inhibited NF-κB, Wnt, and YAP pathways and exhibited synergic effects on killing TNBC bulk tumor and CSCs. This combination nanotherapy evaluated with a PDX model may lead to an effective treatment of patients with TNBC.

Co-inhibition of mTORC1, HDAC and ESR1α retards the growth of triple-negative breast cancer and suppresses cancer stem cells.

Triple-negative breast cancer (TNBC) is the most refractory subtype of breast cancer. It causes the majority of breast cancer-related deaths, which has been largely associated with the plasticity of tumor cells and persistence of cancer stem cells (CSCs). Conventional chemotherapeutics enrich CSCs and lead to drug resistance and disease relapse. Development of a strategy capable of inhibiting both bulk and CSC populations is an unmet medical need. Inhibitors against estrogen receptor 1, HDACs, or mTOR have been studied in the treatment of TNBC; however, the results are inconsistent. In this work, we found that patient TNBC samples expressed high levels of mTORC1 and HDAC genes in comparison to luminal breast cancer samples. Furthermore, co-inhibition of mTORC1 and HDAC with rapamycin and valproic acid, but neither alone, reproducibly promoted ESR1 expression in TNBC cells. In combination with tamoxifen (inhibiting ESR1), both S6RP phosphorylation and rapamycin-induced 4E-BP1 upregulation in TNBC bulk cells was inhibited. We further showed that fractionated CSCs expressed higher levels of mTORC1 and HDAC than non-CSCs. As a result, co-inhibition of mTORC1, HDAC, and ESR1 was capable of reducing both bulk and CSC subpopulations as well as the conversion of fractionated non-CSC to CSCs in TNBC cells. These observations were partially recapitulated with the cultured tumor fragments from TNBC patients. Furthermore, co-administration of rapamycin, valproic acid, and tamoxifen retarded tumor growth and reduced CD44high/+/CD24low/- CSCs in a human TNBC xenograft model and hampered tumorigenesis after secondary transplantation. Since the drugs tested are commonly used in clinic, this study provides a new therapeutic strategy and a strong rationale for clinical evaluation of these combinations for the treatment of patients with TNBC.