The Role of CD4/6 Inhibitors in Breast Cancer Treatment.

Over the last decade, treatment paradigms for breast cancer have undergone a renaissance, particularly in hormone-receptor-positive/HER2-negative breast cancer. These revolutionary therapies are based on the selective targeting of aberrancies within the cell cycle. This shift towards targeted therapies has also changed the landscape of disease monitoring. In this article, we will review the fundamentals of cell cycle progression in the context of the new cyclin-dependent kinase inhibitors. In addition to discussing the currently approved cyclin-dependent kinase inhibitors for breast cancer, we will explore the ongoing development and search for predictive biomarkers and modalities to monitor treatment.

Atraumatic Splenic Rupture: A Notable Complication of Rivaroxaban Use.

Direct oral anticoagulants (DOACs) are well known to be associated with bleeding complications. However, little is known about their association with atraumatic splenic rupture, a potentially fatal condition. We present the case of a 73-year-old female with paroxysmal atrial fibrillation managed with rivaroxaban who developed a spontaneous atraumatic splenic rupture. This highlights the importance of recognizing this complication in patients without previous risk factors, such as abdominal trauma or infiltrative splenic disease, who are under anticoagulation with DOACs. There is a strong need for further research on this complication's underlying mechanism and management.

Functional Quadriplegia as an Initial Presentation of Severe Rheumatoid Arthritis.

Rheumatoid arthritis is a chronic inflammatory condition with many manifestations primarily presenting in older female patients with joint stiffness. Quadriplegia associated with rheumatoid arthritis is common and can occur secondary to spinal cord compression from atlantoaxial dislocation. In contrast, functional quadriplegia is rare and has not been previously reported as an initial manifestation of rheumatoid arthritis. We report the case of a 56-year-old male with a past medical history of carotid artery stenosis, hypertension, and tobacco and alcohol misuse who presented to the emergency department with a five-month history of progressive bilateral shoulder pain and weakness resulting in functional quadriplegia. The patient required inpatient hospital admission for further evaluation of his functional quadriplegia and associated symptoms. His workup was significant for rheumatoid arthritis, and he was successfully treated with high-dose steroids and received physical and occupational therapy during admission. Prior to discharge, the patient was initiated on methotrexate therapy and appointed a follow-up with primary care and rheumatology. The purpose of this study is to facilitate early clinical recognition of a common disease with unique and underreported symptomatology.

Outcomes of Minority COVID-19 patients managed with ECMO: A single-center experience.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has significantly burdened the global healthcare system since December 2019. Minority populations are found to have a higher incidence of hospitalization and higher mortality when compared to Caucasians. Extracorporeal membrane oxygenation (ECMO) is reserved for COVID-19 patients who develop respiratory failure refractory to conventional management. To our knowledge, no data has been reported on outcome differences between Minority COVID-19 patients and Caucasian COVID-19 patients managed with ECMO. We aimed to investigate the outcome differences between these two groups. METHODS: Our retrospective cohort study had 23 adults (aged 18 and older) diagnosed with COVID-19 by polymerase chain reaction. All patients developed acute respiratory distress syndrome (ARDS), refractory to conventional treatment, and were managed on ECMO support. The primary outcome of interest was mortality; the secondary outcome was the rate of ECMO-related complications. RESULTS: The overall mortality rate of our study was higher (70%) than other reports of the COVID-19 population on ECMO. Caucasians in our study had more severe respiratory acidosis with carbon dioxide retention and appeared to have a higher mortality rate of 85.7% compared to Minorities (62.5%). No differences in complication rates between these two groups were identified. CONCLUSIONS: Our cohort revealed a high overall mortality rate of COVID-19 patients on ECMO support. The Caucasian group was observed to have higher mortality than the Minority group. The high overall mortality was likely attributed to the Caucasian group, which had more severe respiratory acidosis before ECMO initiation, a known predictor of poor prognosis in ARDS patients. Our cohort's ethnic composition may also partially explain the high mortality rate since COVID-19 Minorities are reported to have worse outcomes than Caucasians. Larger and randomized studies are needed to investigate further the mortality and complication differences between Minority and Caucasian patients diagnosed with COVID-19 and managed by ECMO.

Case Series: The Coexistence of Thrombocytopenia and Thromboembolism in COVID-19 Patients on ECMO: A Case Series and Literature Review.

Thrombocytopenia and thromboembolism are common complications in coronavirus disease 2019 (COVID-19) patients. The fact that COVID-19 patients develop both thrombocytopenia and thromboembolism has been observed, and multiple studies have investigated the underlying pathophysiology. Extracorporeal membrane oxygenation (ECMO) is reserved for COVID-19 patients who develop respiratory failure and not respond to conventional mechanical ventilation. ECMO induces thromboembolism and raises the incidence of developing thromboembolic events in COVID-19 patients. Here, we report the hospital courses and outcomes of three COVID-19 patients who were treated with ECMO, then developed both thrombocytopenia and thromboembolism. The coexistence of thrombocytopenia and thromboembolism challenges the clinical treatment strategy, including the decision of initiating anticoagulation. Based on current data, anticoagulation is recommended to all hospitalized COVID-19 patients unless there is active bleeding, previous bleeding history within 3 days, or platelet count is lower than 30,000 cells/µl. Further investigation into the mechanisms and implications of thrombocytopenia and thromboembolism in patients with COVID-19 pneumonia will lead to significantly improved outcomes and prognosis for the patients.

Allergic airway inflammation disrupts interleukin-17 mediated host defense against streptococcus pneumoniae infection.

Despite decreasing rates of invasive pneumococcal disease caused by vaccine serotypes, the prevalence of invasive pneumococcal pneumonia in asthmatic patients remains high. However, little is known about the mechanisms underlying the susceptibility of the asthmatic airway to bacterial infections. In this study, we used a combined model of allergic airway inflammation and Streptococcus pneumoniae lung infection to investigate the association between persistent allergic inflammation in the airway and antibacterial host defenses against S. pneumoniae. When challenged with S. pneumoniae, allergic mice exhibited higher airway bacterial burdens, greater eosinophil infiltration, lower neutrophil infiltration, and more severe structural damage than non-allergic mice. In sensitized mice, S. pneumoniae infection elicited higher IL-4 but lower IFN-γ, IL-17 and defensin-ß2 expression than in control mice. These results indicate that persistent allergic inflammation impaired airway host defense against S. pneumoniae is associated with the insufficient IL-17 responses. To elicit IL-17 induced-anti-bacterial immune responses, mice were intranasally immunized with rIL-17. Immunized mice exhibited fewer bacterial colonies in the respiratory tract and less severe lung pathology than unimmunized mice. rIL-17 contributed to airway host defense enhancement and innate immune response promotion, which was associated with increased IL-23, MIP-2 and defensin-ß2 expression. Administration of exogenous IL-17 (2 µg/mouse) suppressed eosinophil-related immune responses. The results demonstrate IL-17 plays a key role in host defenses against bacterial infection in allergic airways and suggest that exogenous IL-17 administration promotes the anti-becterial immune responses and attenuates the existed allergic inflammation.

Involvement of DNA-PKcs in the type I IFN response to CpG-ODNs in conventional dendritic cells in TLR9-dependent or -independent manners.

CpG-ODNs activate dendritic cells (DCs) to produce interferon alpha (IFNα) and beta (IFNß). Previous studies demonstrated that Toll-like receptor 9 (TLR9) deficient DCs exhibited a residual IFNα response to CpG-A, indicating that yet-unidentified molecules are also involved in induction of IFNα by CpG-A. Here, we report that the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) but not Ku70 deficient BMDCs showed defective IFNα and IFNß responses to CpG-A or CpG-B. Loss of both DNA-PKcs and TLR9 further reduced the IFNα response to CpG-A. These DNA-PKcs and TLR9 effects were mediated by their downstream Akt/mTORC1 pathway and downstream events IRAK1 and IKKα. Loss of DNA-PKcs, TLR9, MyD88 or IRAK4 impaired phosphorylation of Akt(S473), S6K, S6, IRAK1, or IKKα in BMDCs in response to CpG-ODNs. The residual IFNα and IFNß in DNA-PKcs-deficient BMDCs were partially responsible for the induction of IL-6 and IL-12 by CpG-ODNs and their stimulatory effect was blocked by IFNAR1 neutralizing antibodies. Further analysis indicated that CpG-ODN associated with DNA-PKcs and Ku70, and induced DNA-PKcs's interaction with TRAF3. Intriguingly, DNA-PKcs but not Ku70 expression level was reduced in TLR9-deficient BMDCs. Taken together, our data suggest that DNA-PKcs is an important mediator in the type I IFN response to CpG-ODNs in TLR9-dependent or -independent fashions.