Targeting a lineage-specific PI3Kɣ-Akt signaling module in acute myeloid leukemia using a heterobifunctional degrader molecule.

Dose-limiting toxicity poses a major limitation to the clinical utility of targeted cancer therapies, often arising from target engagement in nonmalignant tissues. This obstacle can be minimized by targeting cancer dependencies driven by proteins with tissue-restricted and/or tumor-restricted expression. In line with another recent report, we show here that, in acute myeloid leukemia (AML), suppression of the myeloid-restricted PIK3CG/p110γ-PIK3R5/p101 axis inhibits protein kinase B/Akt signaling and compromises AML cell fitness.

Cooperative regulation of coupled oncoprotein synthesis and stability in triple-negative breast cancer by EGFR and CDK12/13.

Evidence has long suggested that epidermal growth factor receptor (EGFR) may play a prominent role in triple-negative breast cancer (TNBC) pathogenesis, but clinical trials of EGFR inhibitors have yielded disappointing results. Using a candidate drug screen, we identified that inhibition of cyclin-dependent kinases 12 and 13 (CDK12/13) dramatically sensitizes diverse models of TNBC to EGFR blockade. This combination therapy drives cell death through the 4E-BP1-dependent suppression of the translation and translation-linked turnover of driver oncoproteins, including MYC.

CBF-Beta Mitigates PI3K-Alpha-Specific Inhibitor Killing through PIM1 in PIK3CA-Mutant Gastric Cancer.

Unlabelled: PIK3CA is the second most mutated gene in cancer leading to aberrant PI3K/AKT/mTOR signaling and increased translation, proliferation, and survival. Some 4%-25% of gastric cancers display activating PIK3CA mutations, including 80% of Epstein-Barr virus-associated GCs. Small molecules, including pan-PI3K and dual PI3K/mTOR inhibitors, have shown moderate success clinically, due to broad on-target/off-tissue effects.

P2RY2-AKT activation is a therapeutically actionable consequence of XPO1 inhibition in acute myeloid leukemia.

Selinexor is a first-in-class inhibitor of the nuclear exportin XPO1 that was recently approved by the US Food and Drug Administration for the treatment of multiple myeloma and diffuse large B-cell lymphoma. In relapsed/refractory acute myeloid leukemia (AML), selinexor has shown promising activity, suggesting that selinexor-based combination therapies may have clinical potential. Here, motivated by the hypothesis that selinexor's nuclear sequestration of diverse substrates imposes pleiotropic fitness effects on AML cells, we systematically catalog the pro- and anti-fitness consequences of selinexor treatment.

Small-molecule targeted therapies induce dependence on DNA double-strand break repair in residual tumor cells.

Residual cancer cells that survive drug treatments with targeted therapies act as a reservoir from which eventual resistant disease emerges. Although there is great interest in therapeutically targeting residual cells, efforts are hampered by our limited knowledge of the vulnerabilities existing in this cell state. Here, we report that diverse oncogene-targeted therapies, including inhibitors of epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), KRAS, and BRAF, induce DNA double-strand breaks and, consequently, ataxia-telangiectasia mutated (ATM)-dependent DNA repair in oncogene-matched residual tumor cells.

Pharmacogenomics in Asia: a systematic review on current trends and novel discoveries.

While early pharmacogenomic studies have primarily been carried out in Western populations, there has been a notable increase in the number of Asian studies over the past decade. We systematically reviewed all pharmacogenomic studies conducted in Asia published before 2016 to highlight trends and identify research gaps in Asia. We observed that pharmacogenomic research in Asia was dominated by larger developed countries, notably Japan and Korea, and mainly driven by local researchers.

Procedural training opportunities for basic pediatric trainees during a 6-month rotation in a level III perinatal centre in Australia.

Objective: We aimed to evaluate the procedural training opportunities for basic paediatric trainees in a large tertiary perinatal centre in Australia, to facilitate a realistic expectation of the procedural skills acquired during a 6-month training period.

Methods: A prospective study in which all neonatal registrars and fellows anonymously documented their opportunities for procedural practice (including IV cannulation, intubation, umbilical lines insertion etc) for each shift during a calender month. Based on the averaged number of each shift type worked in a 6-month rotation, the total exposure to each procedure for one 6-month rotation was calculated.

Dry lung syndrome: a distinct clinical entity.

Infants with preterm prolonged rupture of membranes can present with immediate onset of pulmonary insufficiency and need aggressive ventilatory support. Dry lung syndrome remains an under-recognised clinical entity and very few cases are reported in the literature, though a working definition has been previously proposed. The proposed underlying etiopathogenesis for this is functional hypoplasia of the lung where higher than usual ventilatory pressure for initial 1-2 days can improve oxygenation.