Synaptic inputs from different brain areas are often targeted to distinct regions of neuronal dendritic arbors. Inputs to proximal dendrites usually produce large somatic EPSPs that efficiently ...trigger action potential (AP) output, whereas inputs to distal dendrites are greatly attenuated and may largely modulate AP output. In contrast to most other cortical and hippocampal neurons, hippocampal CA2 pyramidal neurons show unusually strong excitation by their distal dendritic inputs from entorhinal cortex (EC). In this study, we demonstrate that the ability of these EC inputs to drive CA2 AP output requires the firing of local dendritic Na
spikes. Furthermore, we find that CA2 dendritic geometry contributes to the efficient coupling of dendritic Na
spikes to AP output. These results provide a striking example of how dendritic spikes enable direct cortical inputs to overcome unfavorable distal synaptic locale to trigger axonal AP output and thereby enable efficient cortico-hippocampal information flow.
The hippocampal CA3 region is classically viewed as a homogeneous autoassociative network critical for associative memory and pattern completion. However, recent evidence has demonstrated a striking ...heterogeneity along the transverse, or proximodistal, axis of CA3 in spatial encoding and memory. Here we report the presence of striking proximodistal gradients in intrinsic membrane properties and synaptic connectivity for dorsal CA3. A decreasing gradient of mossy fiber synaptic strength along the proximodistal axis is mirrored by an increasing gradient of direct synaptic excitation from entorhinal cortex. Furthermore, we uncovered a nonuniform pattern of reactivation of fear memory traces, with the most robust reactivation during memory retrieval occurring in mid-CA3 (CA3b), the region showing the strongest net recurrent excitation. Our results suggest that heterogeneity in both intrinsic properties and synaptic connectivity may contribute to the distinct spatial encoding and behavioral role of CA3 subregions along the proximodistal axis.
•CA3 shows a marked proximodistal gradient in intrinsic and synaptic properties•Mossy fiber and direct cortical inputs show opposing gradients of synaptic strength•CA3b has the strongest recurrent excitation because of reduced inhibition•This connectivity can explain robust CA3b reactivation during fear memory retrieval
Sun et al. report marked proximodistal gradients in dorsal CA3 neuron intrinsic excitability and synaptic connectivity, with a reduced recurrent I/E ratio in mid-CA3 (CA3b) leading to its stronger net excitation and memory reactivation. This study complements recent findings on CA3 heterogeneity in spatial encoding and behaviors.
The heterogeneity of the breast tumor microenvironment (TME) may contribute to the lack of durable responses to immune checkpoint blockade (ICB); however, mouse models to test this are currently ...lacking. Proper selection and use of preclinical models are necessary for rigorous, preclinical studies to rapidly move laboratory findings into the clinic.
Three versions of a common syngeneic model derived from the MMTV-PyMT autochthonous model were generated by inoculating 1E6, 1E5, or 1E4 cells derived from the MMTV-PyMT mouse into wildtype recipient mice. To elucidate how tumor latency and TME heterogeneity contribute to ICB resistance, comprehensive characterization of the TME using quantitative flow-cytometry and RNA expression analysis (NanoString) was performed. Subsequently, response to ICB was tested. These procedures were repeated using the EMT6 breast cancer model.
The 3 syngeneic versions of the MMTV-PyMT model had vastly different TMEs that correlated to ICB response. The number of cells used to generate syngeneic tumors significantly influenced tumor latency, infiltrating leukocyte populations, and response to ICB. These results were confirmed using the EMT6 breast cancer model. Compared to the MMTV-PyMT autochthonous model, all 3 MMTV-PyMT syngeneic models had significantly more tumor-infiltrating lymphocytes (TILs; CD3
, CD4
, and CD8
) and higher proportions of PD-L1-positive myeloid cells, whereas the MMTV-PyMT autochthonous model had the highest frequency of myeloid cells out of total leukocytes. Increased TILs correlated with response to anti-PD-L1 and anti-CTLA-4 therapy, but PD-L1expression on tumor cells or PD-1 expression of T cells did not.
These studies reveal that tumor cell number correlates with tumor latency, TME, and response to ICB. ICB-sensitive and resistant syngeneic breast cancer models were identified, in which the 1E4 syngeneic model was most resistant to ICB. Given the lack of benefit from ICB in breast cancer, identifying robust murine models presented here provides the opportunity to further interrogate the TME for breast cancer treatment and provide novel insights into therapeutic combinations to overcome ICB resistance.
Although the main focus of immuno-oncology has been manipulating the adaptive immune system, harnessing both the innate and adaptive arms of the immune system might produce superior tumour reduction ...and elimination. Tumour-associated macrophages often have net pro-tumour effects, but their embedded location and their untapped potential provide impetus to discover strategies to turn them against tumours. Strategies that deplete (anti-CSF-1 antibodies and CSF-1R inhibition) or stimulate (agonistic anti-CD40 or inhibitory anti-CD47 antibodies) tumour-associated macrophages have had some success. We hypothesized that pharmacologic modulation of macrophage phenotype could produce an anti-tumour effect. We previously reported that a first-in-class selective class IIa histone deacetylase (HDAC) inhibitor, TMP195, influenced human monocyte responses to the colony-stimulating factors CSF-1 and CSF-2 in vitro. Here, we utilize a macrophage-dependent autochthonous mouse model of breast cancer to demonstrate that in vivo TMP195 treatment alters the tumour microenvironment and reduces tumour burden and pulmonary metastases by modulating macrophage phenotypes. TMP195 induces the recruitment and differentiation of highly phagocytic and stimulatory macrophages within tumours. Furthermore, combining TMP195 with chemotherapy regimens or T-cell checkpoint blockade in this model significantly enhances the durability of tumour reduction. These data introduce class IIa HDAC inhibition as a means to harness the anti-tumour potential of macrophages to enhance cancer therapy.
Since 2011, more women than men have graduated from medical school, yet there remains a paucity of female physicians in surgical specialties. After the 2018 Neurosurgery Match, only 17.5% of ...neurosurgery residents are women. Previous literature documented gender inequality, poor medical school exposure, and lack of female mentorship as reasons for this disparity. We sought to further explore factors that deter female medical students from pursuing neurosurgery.
A comprehensive survey was created and distributed to the 2017–2018 Rutgers New Jersey Medical School student body, requesting anonymous input from female medical students.
Of 104 female respondents, 26.9% had considered neurosurgery as a career and felt dissuaded because of their gender. Of respondents, 88% did not have a senior female medical student pursuing neurosurgery or a female neurosurgical resident as a mentor. More than half of respondents disagreed that they would be dissuaded from a field if they did not have a female mentor. The 88.46% of women who felt that there was a glass ceiling in medicine were also more likely to feel that they would face inequality and adversity that would inhibit training in a male-dominated field. Women who described themselves as seeking challenging and competitive careers strongly felt that they would benefit from exposure to surgical subspecialties during their preclinical years.
Female medical students remain resilient, ambitious, interested in competitive specialties, and eager to explore surgical subspecialties during preclinical years. A multifaceted approach is imperative to recruit and retain qualified women interested in neurosurgery.
Women constitute a minority (9.2%) of academic neurosurgeons. We previously found that women in academic medicine are disadvantaged in funding and career advancement opportunities. We hypothesized ...that women are also underrepresented at neurosurgical society conferences.
Programs from the 2014–2018 meetings of the Congress of Neurological Surgeons (CNS), American Association of Neurological Surgery (AANS), and North American Skull Base Society (NASBS) were analyzed. Demographic data, including name, gender, and geographic region of practice, were collected for speaker, moderator, or leadership positions. χ2 statistical analysis was performed for difference in gender representation across all opportunity spots.
In the period 2014–2018, there was no female presidents or honored guest at any academic meetings analyzed; 53.8% of executive committees comprised all men. Women often constituted a minority (<15%) of speakers and moderators at CNS, AANS, and NASBS meetings: speakers (% female, range), 8.6 (5.5–11.7), 13.6 (10.1–19.7), and 10.5 (5.6–16.6); moderators (% female, range), 7.8 (0–14.3), 23.0 (81.3–91.3), and 13.0 (8.6–18.7). Conference panels frequently comprised all men (58% CNS, 20.7% AANS, 61% NASBS). χ2 analysis found a disparity in male and female participation across all opportunity spots (P = 0.002). Additionally, female participants are often repeated, decreasing total number of unique women participating. There was no significant increase in female participation across the study period.
In 2014–2018, underrepresentation of women in national neurosurgical conferences either matched or exceeded the baseline gender disparity seen in academic neurosurgery. We discussed potential causes of and strategies to address these findings.
•Mean of total NIH grants were significantly larger for men PIs in neurosurgery compared to their women counterparts.•Women significantly exceeded men in mean funding per grant at the level of ...associate professor.•Men comprised the majority of PIs with NIH Grant Funding in neurological surgery departments.•Women had, on average, less length of publication years and lower h-indices compared to their male counterparts.
Research productivity is a vital component to an academic neurosurgeon’s career. We sought to evaluate gender differences in NIH funding among faculty in neurological surgery departments. NIH funding awarded to PIs of neurological surgery departments from 2014 to 2019 were obtained and analyzed for gender differences in funding trends, with attention to terminal degree and academic rank, as well as publication range in length of years and h-index. 79.4% of all NIH grants were awarded to male PIs, with the remaining 20.5% given to their female counterparts. Mean of the total NIH grants awarded to men was significantly higher at $1,796,684 (± Standard Error of Mean (SEM) $155,849, IQR: $1,759,250) compared to women at $1,151,968 (± SEM $137,914, IQR: $1,388,538) (P = 0.022). Mean NIH funding per grant for men was $365,760 (± SEM: $39,592, IQR: $189,692) and for women was $292,912 (± SEM: 28,239, IQR: $283,177). Differences in mean NIH funding per grant approached but did not reach statistical significance between men and women (P = 0.122). When stratified for academic rank, there was a significant difference in mean NIH funding per grant between men and women on the associate professor level (p < 0.005), with women exceeding men in funding at this academic level, with other academic ranks remaining non-significant. Overall, male neurosurgeons receive significantly more total NIH grant funding than their female counterparts, except at the level of associate professor where women were found to surpass men.
Abstract
Manipulation of the innate immune system is a relatively understudied strategy for anti-cancer immunotherapy. The current focus on immunotherapy is centered on the adaptive immune system. ...However, there is growing evidence that manipulation of the innate immune system, including macrophages, is also a promising method to combat cancer.
Tumor associated macrophages (TAMs) are one of the major infiltrating leukocyte populations associated with solid tumors. There are two major types of macrophages: classically activated macrophages, which can kill bacteria, pathogens, and similarly tumor cells; and alternatively activated macrophages which facilitate wound repair and are generally found in the tumor microenvironment. TAMs are generally alternatively activated cells with immunosuppressive properties that have been shown to enhance tumorogenesis by facilitating metastasis, angiogenesis, and inhibiting a protecting adaptive immune response. The presence of macrophages in the tumor microenvironment correlates with poor prognosis. Here we describe a novel, first in class compound that activates macrophages to an anti-tumor phenotype. While this compound has no direct cytotoxic activity, we show in the PyMT mouse model of breast cancer that breast tumors regress in response to therapy in a manner dependent on myeloid cells. Through the use of flow cytometry, we have been able to identify different subpopulations of TAMs using the markers CD45, MHCII, and CD11b. Correlating with tumor regression, we see an increase in PARP and cleaved caspase 3, indicating apoptotic cell death. Here we show that a novel compound effectively polarize macrophages to an anti-tumor phenotype to induce tumor regression. This strategy may have great therapeutic promise.
Citation Format: Alaba O. Sotayo, Jennnifer L. Guerriero, Holly E. Ponichtera, Anthony G. Letai. Polarizing tumor associated macrophages (TAMs) towards an anti-tumor phenotype with a novel compound reveals a new subset of TAMs within breast tumors which facilitate tumor regression. abstract. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5030. doi:10.1158/1538-7445.AM2015-5030
Abstract
Cancer immuno-therapies targeting components of the immune system have shown great promise for the treatment of various forms of cancer. Most of the immuno-therapies currently under trial ...intervene in adaptive immune cell pathways; however, the innate immune system has also recently been shown to play a potent immunomodulatory role in the tumor microenvironment. Tumor associated macrophages (TAMs) compose up to 50% of tumor volume. Presently, we demonstrate that administration of a novel compound stimulates rapid tumor regression that is associated with the infiltration of F4/80+ macrophages into tumors in the MMTV-PyMT murine model of breast cancer. A significant increase in tumor-infiltrating macrophages was visible by immunohistochemistry after five days of treatment and macrophages were necessary for tumor regression as demonstrated by cell depletion assays in vivo. Of note, macrophage infiltration correlated with an increase in tumor cell death as shown by elevated expression of the apoptotic protein cleaved-caspase-3 (CC3); conversely, cell proliferation factor Ki67 was decreased. Additionally, compound-treated animals exhibited striking changes in tumor vascularization, with a marked decrease in overall endothelial cell marker expression as displayed by immunohistochemistry. Taken together, these findings reveal a novel role for macrophages in breast tumor regression during treatment with a novel compound that alters the tumor microenvironment.
Citation Format: Holly E. Ponichtera, Jennifer L. Guerriero, Alaba O. Sotayo, Anthony Letai. Novel compound elicits anti-tumor macrophages associated with tumor regression in breast cancer. abstract. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 460. doi:10.1158/1538-7445.AM2015-460
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