Corticothalamic Axons Are Essential for Retinal Ganglion Cell Axon Targeting to the Mouse Dorsal Lateral Geniculate Nucleus.

UNLABELLED: Retinal ganglion cells (RGCs) relay information about the outside world to multiple subcortical targets within the brain. This information is either used to dictate reflexive behaviors or relayed to the visual cortex for further processing. Many subcortical visual nuclei also receive descending inputs from projection neurons in the visual cortex. Most areas receive inputs from layer 5 cortical neurons in the visual cortex but one exception is the dorsal lateral geniculate nucleus (dLGN), which receives layer 6 inputs and is also the only RGC target that sends direct projections to the cortex. Here we ask how visual system development and function changes in mice that develop without a cortex. We find that the development of a cortex is essential for RGC axons to terminate in the dLGN, but is not required for targeting RGC axons to other subcortical nuclei. RGC axons also fail to target to the dLGN in mice that specifically lack cortical layer 6 projections to the dLGN. Finally, we show that when mice develop without a cortex they can still perform a number of vision-dependent tasks. SIGNIFICANCE STATEMENT: The dorsal lateral geniculate nucleus (dLGN) is a sensory thalamic relay area that receives feedforward inputs from retinal ganglion cells (RGCs) in the retina, and feed back inputs from layer 6 neurons in the visual cortex. In this study we examined genetically manipulated mice that develop without a cortex or without cortical layer 6 axonal projections, and find that RGC axons fail to project to the dLGN. Other RGC recipient areas, such as the superior colliculus and suprachiasmatic nucleus, are targeted normally. These results provide support for a new mechanism of target selection that may be specific to the thalamus, whereby descending cortical axons provide an activity that promotes feedforward targeting of RGC axons to the dLGN.

Vismodegib or cixutumumab in combination with standard chemotherapy for patients with extensive-stage small cell lung cancer: A trial of the ECOG-ACRIN Cancer Research Group (E1508).

BACKGROUND: Preclinical targeting of the hedgehog pathway by vismodegib and of insulin-like growth factor 1 receptor by cixutumumab enhances the efficacy of chemotherapy and also demonstrates activity against the tumor cell fraction responsible for disease recurrence in small cell lung cancer. METHODS: Patients with newly diagnosed extensive-stage small cell lung cancer (SCLC-ED) were randomized to receive four 21-day cycles of cisplatin and etoposide alone (cisplatin at 75 mg/m(2) on day 1 and etoposide at 100 mg/m(2) on days 1-3; arm A) or in combination with either vismodegib (150 mg/d by mouth; arm B) or cixutumumab (6 mg/kg/wk intravenously on day 1; arm C). The primary endpoint was progression-free survival (PFS). Circulating tumor cells (CTCs) were isolated/enumerated with the Veridex CellSearch platform at the baseline. RESULTS: One hundred fifty-two eligible patients were treated. Patient demographics and disease characteristics were well balanced between the 3 arms except for the higher rate with a performance status of 0 in arm B (P = .03). The median PFS times in arms A, B, and C were 4.4, 4.4, and 4.6 months, respectively; the median overall survival (OS) times were 8.8, 9.8, and 10.1 months, respectively; and the response rates were 48%, 56%, and 50%, respectively. None of the comparisons of these outcomes were statistically significant. The median OS was 10.5 months for those with low CTC counts (≤100/7.5 mL) at baseline and 7.2 months for those with high CTC counts (hazard ratio, 1.74; P = .006). CONCLUSIONS: There was no significant improvement in PFS or OS with the addition of either vismodegib or cixutumumab to chemotherapy in patients with SCLC-ED. A low baseline CTC count was associated with a favorable prognosis. Cancer 2016;122:2371-2378. © 2016 American Cancer Society.

Randomized Study of Temozolomide or Temozolomide and Capecitabine in Patients With Advanced Pancreatic Neuroendocrine Tumors (ECOG-ACRIN E2211).

PURPOSE: Patients with advanced pancreatic neuroendocrine tumors (NETs) have few treatment options that yield objective responses. Retrospective and small prospective studies suggest that capecitabine and temozolomide are associated with high response rates (RRs) and long progression-free survival (PFS). PATIENTS AND METHODS: E2211 was a multicenter, randomized, phase II trial comparing temozolomide versus capecitabine/temozolomide in patients with advanced low-grade or intermediate-grade pancreatic NETs. Key eligibility criteria included progression within the preceding 12 months and no prior temozolomide, dimethyl-triazeno-imidazole-carboxamide or dacarbazine, capecitabine or fluorouracil. The primary end point was PFS; secondary endpoints were overall survival, RR, safety, and methylguanine methyltransferase (MGMT) by immunohistochemistry and promoter methylation. RESULTS: A total of 144 patients were enrolled between April 2013 and March 2016 to temozolomide (n = 72) or capecitabine and temozolomide (n = 72); the primary analysis population included 133 eligible patients. At the scheduled interim analysis in January 2018, the median PFS was 14.4 months for temozolomide versus 22.7 months for capecitabine/temozolomide (hazard ratio = 0.58), which was sufficient to reject the null hypothesis for the primary end point (stratified log-rank P = .022). In the final analysis (May 2021), the median overall survival was 53.8 months for temozolomide and 58.7 months for capecitabine/temozolomide (hazard ratio = 0.82, P = .42). MGMT deficiency was associated with response. CONCLUSION: The combination of capecitabine/temozolomide was associated with a significant improvement in PFS compared with temozolomide alone in patients with advanced pancreatic NETs. The median PFS and RR observed with capecitabine/temozolomide are the highest reported in a randomized study for pancreatic NETs. MGMT deficiency was associated with response, and although routine MGMT testing is not recommended, it can be considered for select patients in need of objective response (ClinicalTrials.gov identifier: NCT01824875).

Helicobacter pylori requires TlpD-driven chemotaxis to proliferate in the antrum.

Different disease outcomes of Helicobacter pylori infection correlate with distinct inflammation patterns. These different inflammatory distributions may be initiated by differences in bacterial localization. One H. pylori property known to affect murine stomach localization is chemotaxis, the ability to move in response to chemical cues. In this report, we used nonchemotactic mutants (Che(-)) to analyze whether chemotaxis is required for initial colonization of particular stomach regions or for subsequent growth therein. We found that H. pylori behaves differently in the corpus, antrum, and corpus-antrum transition zone subregions of the stomach. This outcome suggests that these regions contain unique chemotactic signals. In the corpus, H. pylori utilizes chemotaxis for initial localization but not for subsequent growth. In contrast, in the antrum and the corpus-antrum transition zone, chemotaxis does not help initial colonization but does promote subsequent proliferation. To determine which chemoreceptor is responsible for the corpus-antrum phenotypes, we infected mice with strains lacking each chemoreceptor. Strains lacking TlpA, TlpB, or TlpC displayed only modest deviations from the wild-type phenotype, while strains lacking TlpD resembled the Che(-) mutant in their antral colonization defect and fared even worse than the Che(-) mutant in the corpus. Additional analysis showed that inflammation is worse in the antrum than in the corpus in both wild-type and Che(-) mutant infections. These results suggest that chemotaxis, specifically, that controlled by TlpD, is necessary for H. pylori to survive or grow in the environment of increased inflammation in the antrum.

GammaTile® brachytherapy in the treatment of recurrent glioblastomas.

BACKGROUND: GammaTile® (GT) is a recent U.S. Food and Drug Administration (FDA) cleared brachytherapy platform. Here, we report clinical outcomes for recurrent glioblastoma patients after GT treatment following maximal safe resection. METHODS: We prospectively followed twenty-two consecutive Isocitrate Dehydrogenase (IDH) wild-type glioblastoma patients (6 O6-Methylguanine-DNA methyltransferase methylated (MGMTm); sixteen MGMT unmethylated (MGMTu)) who underwent maximal safe resection of recurrent tumor followed by GT placement. RESULTS: The cohort consisted of 14 second and eight third recurrences. In terms of procedural safety, there was one 30-day re-admission (4.5%) for an incisional cerebrospinal fluid leak, which resolved with lumbar drainage. No other wound complications were observed. Six patients (27.2%) declined in Karnofsky Performance Score (KPS) after surgery due to worsening existing deficits. One patient suffered a new-onset seizure postsurgery (4.5%). There was one (4.5%) 30-day mortality from intracranial hemorrhage secondary to heparinization for an ischemic limb. The mean follow-up was 733 days (range 279-1775) from the time of initial diagnosis. Six-month local control (LC6) and twelve-month local control (LC12) were 86 and 81%, respectively. Median progression-free survival (PFS) was comparable for MGMTu and MGMTm patients (~8.0 months). Median overall survival (OS) was 20.0 months for the MGMTu patients and 37.4 months for MGMTm patients. These outcomes compared favorably to data in the published literature and an independent glioblastoma cohort of comparable patients without GT treatment. CONCLUSIONS: This clinical experience supports GT brachytherapy as a treatment option in a multi-modality treatment strategy for recurrent glioblastomas.

A Randomized Phase II Study to Determine the Effect of 2 Different Doses of Aflibercept in Patients With Metastatic Renal Cell Carcinoma (ECOG-ACRIN [E4805]).

BACKGROUND: Aflibercept is a recombinantly produced fusion protein that has potent anti-vascular endothelial growth factor (VEGF) activity. We tested whether aflibercept has clinical activity in clear-cell renal cell carcinoma (ccRCC). The recommended phase II dose was 4 mg/kg but several patients (pts) treated at 1 mg/kg showed prolonged progression-free survival. We therefore tested both doses in a parallel group randomized trial. PATIENTS AND METHODS: Eligible pts had histologically confirmed advanced or metastatic ccRCC and previous treatments included exposure to a VEGF receptor tyrosine kinase inhibitor. Pts received aflibercept (either 1 mg/kg or 4 mg/kg) on day 1 of a 14-day cycle until disease progression. Pts randomized to 1 mg/kg could crossover to 4 mg/kg at the time of disease progression. The primary end point was proportion alive and progression-free at 8 weeks. A Simon 2-stage design was used for each arm with 33 and 24 eligible pts per arm enrolled in stages 1 and 2. RESULTS: Ninety-four pts were enrolled, 59 and 35 to 4 mg and 1 mg doses, respectively. Seventy-two percent had 1 previous treatment most commonly sunitinib. Sixteen eligible pts crossed over at the time of disease progression to the 4-mg dose. Most common adverse events were hypertension, proteinuria, and fatigue. Only 4 pts reported Grade 4 or higher toxicity. With 36 of 59 pts (61%) progression-free at 8 weeks, the 4-mg/kg dose met protocol-specified efficacy criteria. CONCLUSION: Aflibercept is active in previously treated ccRCC and might be worthy of further study.

Structural evidence for consecutive Hel308-like modules in the spliceosomal ATPase Brr2.

Brr2 is a DExD/H-box helicase responsible for U4/U6 unwinding during spliceosomal activation. Brr2 contains two helicase-like domains, each of which is followed by a Sec63 domain with unknown function. We determined the crystal structure of the second Sec63 domain, which unexpectedly resembles domains 4 and 5 of DNA helicase Hel308. This, together with sequence similarities between Brr2's helicase-like domains and domains 1-3 of Hel308, led us to hypothesize that Brr2 contains two consecutive Hel308-like modules (Hel308-I and Hel308-II). Our structural model and mutagenesis data suggest that Brr2 shares a similar helicase mechanism with Hel308. We demonstrate that Hel308-II interacts with Prp8 and Snu114 in vitro and in vivo. We further find that the C-terminal region of Prp8 (Prp8-CTR) facilitates the binding of the Brr2-Prp8-CTR complex to U4/U6. Our results have important implications for the mechanism and regulation of Brr2's activity in splicing.