ABSTRACT
Small-cell lung cancer (SCLC) accounts for nearly 15% of all lung cancers. Although patients respond to first-line therapy readily, rapid relapse is inevitable, with few treatment options in the second-line setting. Here, we describe SCLC cell lines harboring amplification of MYC and MYCN, but not MYCL1 nor non-amplified MYC cell lines, exhibit superior sensitivity to treatment with the pan-BET bromodomain protein inhibitor Mivebresib (ABBV-075). Silencing MYC and MYCN partially rescued SCLC cell lines harboring these respective amplifications from the anti-proliferative effects of mivebresib. Further characterization of genome-wide binding of MYC, MYCN, and MYCL1 uncovered unique enhancer and epigenetic preferences. Implications: Our study suggests that chromatin landscapes could establish cell states with unique gene expression programs, conveying sensitivity to epigenetic inhibitors such as mivebresib.
ABSTRACT
Gastrointestinal stromal tumors (GISTs) are soft-tissue sarcomas that can occur anywhere in the digestive tract, with the stomach and small intestine being the most common locations. Because no imaging modalities diagnose GIST unequivocally, histological and immunohistochemical confirmation is usually required. Most GISTs are discovered by chance; hence, determining this condition's actual frequency can be challenging. Since diagnosing the tumor could be difficult, including GIST in the differential diagnosis is crucial. The objective of this review is to explore the multiple treatment options for this tumor and provide clinicians with more information on the evolving treatment modalities, which in the future could be a possible solution to cure GIST ultimately. After exploring several studies, the authors conclude that early detection is critical since the treatment depends on the tumor size, mitotic rate, and location. Medical management using targeted therapy approved by the United States Food and Drug Administration (FDA) include tyrosine kinase inhibitors such as imatinib, sunitinib, and regorafenib. Surgical resection of the tumor is also done in cases with localized tumors. Standard chemotherapy and radiotherapy are not commonly used to treat GIST patients. However, radiotherapy may be used as a palliative therapy to ease pain (such as bone pain) or control bleeding. Additional research is needed to establish potential therapeutic targets that will result in higher and longer-term response rates.
ABSTRACT
Chronic lymphocytic leukemia (CLL) is one of the most commonly occurring types of leukemia among the elderly population, contributing to an increased vulnerability to infections that are especially prolific in the immunosuppressed and the risk of rapid progression of the disease into a more aggressive manifestation of large cell lymphoma, a process called Richter's Transformation (RT). CLL alone predisposes patients to develop infections; however, the additional complication of RT decreases survival and makes the prevention and control of infection for the CLL patient even more challenging. However, research that exists on preventing and controlling infection in CLL patients with RT is relatively limited. In most cases, studies have focused on the prevention of infection in CLL patients in general and with no reference to the progression of RT. Considering the dearth of research on infection prevention and control for patients with CLL complicated by RT specifically, the following review examines existing research in addressing the prevention and control of infection in CLL patients with RT and patients in general. The authors explored multiple databases such as PubMed, Google Scholar, and Science Direct. The ultimate focus of this study was to lay a fundamental understanding in preventing and controlling infection in CLL patients. After analyzing several studies, it can be concluded that identifying infections, even if rare, is a crucial aspect of managing CLL patients. A broad range of differential diagnoses should be sought in cases presenting with refractory CLL as well and management of infections before, during, or after CLL treatment should be considered.
ABSTRACT
Connexin-36 (Cx36) gap junctions (GJs) appear to be involved in the synchronization of GABA interneurons in many brain areas. We have previously identified a population of Cx36-connected ventral tegmental area (VTA) GABA neurons that may regulate mesolimbic dopamine (DA) neurotransmission, a system implicated in reward from both natural behaviors and drugs of abuse. The aim of this study was to determine the effect mefloquine (MFQ) has on midbrain DA and GABA neuron inhibition, and the role Cx36 GJs play in regulating midbrain VTA DA neuron activity in mice. In brain slices from adolescent wild-type (WT) mice the Cx36-selective GJ blocker mefloquine (MFQ, 25 µM) increased VTA DA neuron sIPSC frequency sixfold, and mIPSC frequency threefold. However, in Cx36 KO mice, MFQ only increased sIPSC and mIPSC frequency threefold. The nonselective GJ blocker carbenoxolone (CBX, 100 µM) increased DA neuron sIPSC frequency twofold in WT mice, did not affect Cx36 KO mouse sIPSCs, and did not affect mIPSCs in WT or Cx36 KO mice. Interestingly, MFQ had no effect on VTA GABA neuron sIPSC frequency. We also examined MFQ effects on VTA DA neuron firing rate and current-evoked spiking in WT and Cx36 KO mice, and found that MFQ decreased WT DA neuron firing rate and current-evoked spiking, but did not alter these measures in Cx36 KO mice. Taken together these findings suggest that blocking Cx36 GJs increases VTA DA neuron inhibition, and that GJs play in key role in regulating inhibition of VTA DA neurons. Synapse, 2011. © 2011 Wiley-Liss, Inc.
