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Immune checkpoint blockade has been used to treat breast cancer, but the clinical responses remain relatively poor. We have used the CRISPR-Cas9 kinome knockout library consisting of 763 kinase genes to identify tumor-intrinsic kinases conferring resistance to anti-PD-1 immune checkpoint blockade. We have identified the CDC42BPB kinase as a potential target to overcome the resistance to anti-PD-1 immune checkpoint blockade immunotherapy. We found that CDC42BPB is highly expressed in breast cancer patients who are non-responsive to immunotherapy. Furthermore, a small-molecule pharmacological inhibitor, BDP5290, which targets CDC42BPB, synergized with anti-PD-1 and enhanced tumor cell killing by promoting T cell proliferation in both in vitro and in vivo assays. Moreover, anti-PD-1-resistant breast cancer cells showed higher expression of CDC42BPB, and its inhibition rendered the resistant cells more susceptible to T cell killing in the presence of anti-PD-1. We also found that CDC42BPB phosphorylated AURKA, which in turn upregulated PD-L1 through cMYC. Our results have revealed a robust link between tumor-intrinsic kinase and immunotherapy resistance and have provided a rationale for a unique combination therapy of CDC42BPB inhibition and anti-PD-1 immunotherapy for breast cancer.
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The Nazi regime held power for well over a decade in Germany and were steadfast in their anti-Semitic agenda. Among the massive cohort of immigrants to America were approximately 5056 Jewish physicians, including several highly esteemed neurologists and neuroscientists of the time. Emigrating to a new world proved difficult and provided new challenges by way of language barriers, roadblocks in medical careers, and problems integrating into an alien system of medical training and clinical practice. In this article, the authors examine the tumultuous and accomplished lives of three Jewish German and Austrian neurologists and neuroscientists during the time of the Third Reich who shaped the foundations of neuroanatomy and neuropsychology: Josef Gerstmann, Adolf Wallenberg, and Franz Josef Kallmann. The authors first examine the successful careers of these individuals in Germany and Austria prior to the Third Reich, followed by their journeys to and lives in the United States, to demonstrate the challenges an émigré physician faces for career opportunities and a chance at a new life. This account culminates in a description of these scientists' eponymous syndromes.Although their stories are a testimony to the struggles in Nazi Germany, there are intriguing and notable differences in their ages, ideologies, and religious beliefs, which highlight a spectrum of unique circumstances that impacted their success in the United States. Furthermore, in this account the authors bring to light the original syndromic descriptions: Gerstmann discovered contralateral agraphia and acalculia, right-left confusion, and finger agnosia in patients with dominant angular gyrus damage; Wallenberg described a constellation of symptoms in a patient with stenosis of the posterior inferior cerebellar artery; and Kallmann identified an association between hypogonadotropic hypogonadism and anosmia based on family studies. The article also highlights the unresolved confusions and international controversies about these syndromic descriptions. Still, these unique cerebral syndromes continue to fascinate neurologists and neurosurgeons across the world, from residents in training to practicing clinicians and neuroscientists alike.
Asunto(s)
Emigración e Inmigración/historia , Judíos/historia , Nacionalsocialismo/historia , Neurólogos/historia , Neurociencias/historia , Austria , Alemania , Historia del Siglo XIX , Historia del Siglo XX , Humanos , Masculino , Psiquiatría/historiaRESUMEN
OBJECTIVE: Regular reporting on recruitment of women into neurosurgery is a mechanism to track the progress of minority inclusion and diversity. For more than 20 years, half of US medical students have been women, yet a disproportionate minority pursue a career in neurosurgery. The authors previously published data tracking women in neurosurgery for the prior decade from 2000 to 2009, which showed an increasing match rate of women over time, from 18 women matched at the beginning of the decade to 36 matched at the end. They now present updated data on the matriculation of women into neurosurgical residencies across the most recent decade, from 2010 to 2019. METHODS: Public databases from the Association of American Medical Colleges were analyzed for applicants to neurosurgical residency from 2010 to 2019. Demographic data for those matched was obtained from the American Medical Association Masterfile and analyzed for year of match and gender. Secondary outcomes included program location, age, and gap year(s) between medical school and residency. RESULTS: Women made up 18.8% (394/2094) of residents matched into neurosurgery from 2010 to 2019, compared to 12% during the previous decade. There was an increase in overall match rate of 2.2% per year (male + female) from 2010 to 2019, representing the predicted need for expansion of the neurosurgical workforce to meet national needs. Women made up the majority of this expansion, rising by 5.5% over the time period (p = 0.002), compared to men increasing by 1.4% over the time period (p = 0.096). The percentage of women applicants who matched was 34.4%, compared to men at 38.6% (p = 0.009). There was no significant difference in gender with regard to age, number of gap years, or program location. CONCLUSIONS: The number of women matching into neurosurgery has continued to increase across the last 2 decades. Despite this, there remains significant disparity between the number of men and women matching into neurosurgery. Ongoing mitigation of barriers to recruitment of women into neurosurgery is critical. The authors' data highlight the fact that women are important to fueling the expansion of the neurosurgical workforce.
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Intracranial hemorrhage (ICH) can be a devastating medical event with numerous potential etiologies. In young people under age 40, ruptured vascular malformation is the most common cause of ICH. Without critical review of imaging and laboratory findings and clinical suspicion beyond vascular malformation, alternative etiologies of hemorrhage may be overlooked in the younger age group. Here we present a case of a 22-year-old male presenting with large ICH originally thought secondary to ruptured vascular malformation. After careful review of all imaging and laboratory findings, the patient was found to have hemorrhage secondary to acute promyelocytic leukemia (APL). Though ICH proved fatal in this case, early treatment of acute leukemia with appropriate chemotherapeutic agents and correction of coagulopathy could be life saving for patients with less severe intracranial injury.
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BACKGROUND: Spinal metastases pose significant morbidity. For many histologies, the spine is a frequent site for bone metastases. This predilection is not fully understood, and there are conflicting reports regarding the distribution within the vertebral body itself. Knowing this distribution will give clues as to the underlying biologic reason for this increased incidence in the spine and lead to a better understanding of tumor dispersion and growth. METHODS: We retrospectively examined magnetic resonance imaging scans of patients undergoing radiation to the spine from 2015 to 2017 for spinal metastases. The anatomical distribution of lesions was categorized. Lesions were sorted along the sagittal plane into 5 groups: anterior only, anterior + middle, middle only, posterior + middle, and posterior only. Lesions that covered all groups were discarded. χ2 and post-hoc analyses were used for statistical analyses. RESULTS: Three hundred metastatic lesions were examined in 89 patients; 203 lesions were used for analysis. Sixty-five percent of all lesions were found in posterior only and posterior + middle aspects of the vertebral body (P < 0.0001). This localization was significant regardless of histology: lung (67%, P < 0.0001), kidney (66%, P < 0.0001), sarcoma (67%, P < 0.0001), prostate (63%, P = 0.01), and breast (63%, P = 0.01). This was consistent across thoracic (n = 96) and lumbar (n = 63) regions (72% and 64%, respectively, P < 0.0001). CONCLUSIONS: Metastatic lesions of the thoracolumbar spine have a greater propensity to localize to the posterior aspect of the vertebral body. These data support the hypothesis that there may be differences within the vertebral body leading to differential tumor dispersion and growth.