Endogenous pAKT activity is associated with response to AKT inhibition alone and in combination with immune checkpoint inhibition in murine models of TNBC.

Triple-negative breast cancer (TNBC) is a heterogeneous and challenging-to-treat breast cancer subtype. The clinical introduction of immune checkpoint inhibitors (ICI) for TNBC has had mixed results, and very few patients achieved a durable response. The PI3K/AKT pathway is frequently mutated in breast cancer.

Molecular cartography uncovers evolutionary and microenvironmental dynamics in sporadic colorectal tumors.

Colorectal cancer exhibits dynamic cellular and genetic heterogeneity during progression from precursor lesions toward malignancy. Analysis of spatial multi-omic data from 31 human colorectal specimens enabled phylogeographic mapping of tumor evolution that revealed individualized progression trajectories and accompanying microenvironmental and clonal alterations. Phylogeographic mapping ordered genetic events, classified tumors by their evolutionary dynamics, and placed clonal regions along global pseudotemporal progression trajectories encompassing the chromosomal instability (CIN+) and hypermutated (HM) pathways.

Using behavioral insights to increase the demand for childhood vaccination in low resource settings: Evidence from a randomized controlled trial in Lebanon.

Objective: Lebanon has historically maintained high immunization coverage rates for most routine vaccines. However, an increase in poverty rates coupled with an influx of over a million refugees posed significant challenges to the national immunization program. In response, an accelerated immunization activities (AIA) program, encompassing community-based outreach and referral activities, was launched to increase the demand for childhood vaccination through the public healthcare system.

Parents' Perceptions of Changes in Sleep Duration, Physical Activity, and Sedentary Behavior in Arab Israeli Children during the COVID-19 Outbreak.

The COVID-19 pandemic led many countries to apply lockdown measures that could prevent children from achieving the physical activity, sedentary behavior, and sleep levels suggested for their psychophysical health. The current study tested changes in physical activity, sedentary behavior, and sleep length of children and the incidence of achieving the 24 h movement standards through the limitations of COVID-19. A total of 490 Arab Israeli parents were surveyed.

Dendritic cell therapy augments antitumor immunity triggered by CDK4/6 inhibition and immune checkpoint blockade by unleashing systemic CD4 T-cell responses.

Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy are a mainstay treatment for hormone receptor-positive breast cancer. While their principal mechanism is inhibition of cancer cell proliferation, preclinical and clinical evidence suggests that CDK4/6i can also promote antitumor T-cell responses. However, this pro-immunogenic property is yet to be successfully harnessed in the clinic, as combining CDK4/6i with immune checkpoint blockade (ICB) has not shown a definitive benefit in patients.

Cardamom oil ameliorates behavioral and neuropathological disorders in a rat model of depression induced by reserpine.

Ethnopharmacological Relevance: Depression is a public health problem. Despite the availability of treatment options, its prevalence is increasing. A high rate of treatment failure is often reported, along with considerable side effects associated with synthetic antidepressants.

Novel induction of CD40 expression by tumor cells with RAS/RAF/PI3K pathway inhibition augments response to checkpoint blockade.

Background: While immune checkpoint blockade (ICB) is the current first-line treatment for metastatic melanoma, it is effective for ~ 52% of patients and has dangerous side effects. The objective here was to identify the feasibility and mechanism of RAS/RAF/PI3K pathway inhibition in melanoma to sensitize tumors to ICB therapy.

Methods: Rigosertib (RGS) is a non-ATP-competitive small molecule RAS mimetic.

Inhibition of the PI3K/mTOR Pathway in Breast Cancer to Enhance Response to Immune Checkpoint Inhibitors in Breast Cancer.

Objectives: Inhibition of the PI3K/mTOR pathway suppresses breast cancer (BC) growth, enhances anti-tumor immune responses, and works synergistically with immune checkpoint inhibitors (ICI). The objective here was to identify a subclass of PI3K inhibitors that, when combined with paclitaxel, is effective in enhancing response to ICI.

Methods: C57BL/6 mice were orthotopically implanted with syngeneic luminal/triple-negative-like PyMT cells exhibiting high endogenous PI3K activity.

Metabolic modulation by CDK4/6 inhibitor promotes chemokine-mediated recruitment of T cells into mammary tumors.

Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) delay progression of metastatic breast cancer. However, complete responses are uncommon and tumors eventually relapse. Here, we show that CDK4/6i can enhance efficacy of T cell-based therapies, such as adoptive T cell transfer or T cell-activating antibodies anti-OX40/anti-4-1BB, in murine breast cancer models.

MDM2 antagonists overcome intrinsic resistance to CDK4/6 inhibition by inducing p21.

Intrinsic resistance of unknown mechanism impedes the clinical utility of inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) in malignancies other than breast cancer. Here, we used melanoma patient-derived xenografts (PDXs) to study the mechanisms for CDK4/6i resistance in preclinical settings. We observed that melanoma PDXs resistant to CDK4/6i frequently displayed activation of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway, and inhibition of this pathway improved CDK4/6i response in a p21-dependent manner.

MDM2 Antagonists Counteract Drug-Induced DNA Damage.

Antagonists of MDM2-p53 interaction are emerging anti-cancer drugs utilized in clinical trials for malignancies that rarely mutate p53, including melanoma. We discovered that MDM2-p53 antagonists protect DNA from drug-induced damage in melanoma cells and patient-derived xenografts. Among the tested DNA damaging drugs were various inhibitors of Aurora and Polo-like mitotic kinases, as well as traditional chemotherapy.

Inhibition of MMP-2 and MMP-9 decreases cellular migration, and angiogenesis in in vitro models of retinoblastoma.

Background: Retinoblastoma (Rb) is the most common primary intraocular tumor in children. Local treatment of the intraocular disease is usually effective if diagnosed early; however advanced Rb can metastasize through routes that involve invasion of the choroid, sclera and optic nerve or more broadly via the ocular vasculature. Metastatic Rb patients have very high mortality rates.

Five-year institutional bibliometric profiles for 103 US neurosurgical residency programs.

Object: Various bibliometric indices based on the citations accumulated by scholarly articles, including the h-index, g-index, e-index, and Google's i10-index, may be used to evaluate academic productivity in neurological surgery. The present article provides a comprehensive assessment of recent academic publishing output from 103 US neurosurgical residency programs and investigates intradepartmental publishing equality among faculty members.

Methods: Each institution was considered a single entity, with the 5-year academic yield of every neurosurgical faculty member compiled to compute the following indices: ih(5), cumulative h, ig(5), ie(5), and i10(5) (based on publications and citations from 2009 through 2013).

A novel route to organonitrites by Pd-catalyzed cross-coupling of sodium nitrite and potassium organotrifluoroborates.

Microwave irradiated palladium-catalyzed cross-coupling reaction of potassium styryltrifluoroborates and sodium nitrite gives the corresponding styryl nitrites in high yields. Potassium aryltrifluoroborates also furnish aryl nitrites under same reaction condition. This unprecedented cross-coupling is an interesting development and has the potential to lead to new nitration protocols.