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  • 1
    In: Open Forum Infectious Diseases, Oxford University Press (OUP), Vol. 9, No. 7 ( 2022-07-04)
    Abstract: Patients with coronavirus disease 2019 (COVID-19) admitted to the intensive care unit (ICU) have poor outcomes and frequently develop comorbid conditions, including cytomegalovirus (CMV) reactivation. The implications of CMV reactivation in this setting are unknown. We aimed to investigate if treatment of CMV viremia improved in-hospital mortality in ICU patients with COVID-19. Methods In this single-center retrospective study, we analyzed clinical outcomes in patients diagnosed with COVID-19 pneumonia and CMV viremia admitted to an ICU from March 1, 2020, to April 30, 2021, who either received treatment (ganciclovir and/or valganciclovir) or received no treatment. The primary outcome was all-cause in-hospital mortality. Secondary outcomes were total hospital length of stay (LOS), ICU LOS, requirement for extracorporeal membrane oxygenation (ECMO) support, duration of mechanical ventilation (MV), and predictors of in-hospital mortality. Results A total of 80 patients were included, 43 patients in the treatment group and 37 in the control group. Baseline characteristics were similar in both groups. CMV-treated patients were more likely to test positive for CMV earlier in their course, more likely to be on ECMO, and received higher total steroid doses on average. In-hospital mortality was similar between the 2 groups (37.2% vs 43.2.0%; P = .749). There was no significant difference in hospital LOS, though CMV-treated patients had a longer ICU LOS. Conclusions Treatment of CMV viremia did not decrease in-hospital mortality in ICU patients with COVID-19, but the sample size was limited. CMV viremia was significantly associated with total steroid dose received and longer ICU stay.
    Type of Medium: Online Resource
    ISSN: 2328-8957
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2757767-3
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  • 2
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 19, No. 11 ( 2021-11-01), p. 1929-1945
    Abstract: Resistance to cyclin D-CDK4/6 inhibitors (CDK4/6i) represents an unmet clinical need and is frequently caused by compensatory CDK2 activity. Here we describe a novel strategy to prevent CDK4i resistance by using a therapeutic liposomal:peptide formulation, NP-ALT, to inhibit the tyrosine phosphorylation of p27Kip1(CDKN1B), which in turn inhibits both CDK4/6 and CDK2. We find that NP-ALT blocks proliferation in HR+ breast cancer cells, as well as CDK4i-resistant cell types, including triple negative breast cancer (TNBC). The peptide ALT is not as stable in primary mammary epithelium, suggesting that NP-ALT has little effect in nontumor tissues. In HR+ breast cancer cells specifically, NP-ALT treatment induces ROS and RIPK1-dependent necroptosis. Estrogen signaling and ERα appear required. Significantly, NP-ALT induces necroptosis in MCF7 ESRY537S cells, which contain an ER gain of function mutation frequently detected in metastatic patients, which renders them resistant to endocrine therapy. Here we show that NP-ALT causes necroptosis and tumor regression in treatment naïve, palbociclib-resistant, and endocrine-resistant BC cells and xenograft models, demonstrating that p27 is a viable therapeutic target to combat drug resistance. Implications: This study reveals that blocking p27 tyrosine phosphorylation inhibits CDK4 and CDK2 activity and induces ROS-dependent necroptosis, suggesting a novel therapeutic option for endocrine and CDK4 inhibitor-resistant HR+ tumors.
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2097884-4
    SSG: 12
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  • 3
    Online Resource
    Online Resource
    Oxford University Press (OUP) ; 2019
    In:  American Journal of Clinical Pathology Vol. 152, No. Supplement_1 ( 2019-09-11), p. S121-S121
    In: American Journal of Clinical Pathology, Oxford University Press (OUP), Vol. 152, No. Supplement_1 ( 2019-09-11), p. S121-S121
    Abstract: Neuroendocrine gallbladder neoplasms are rare, comprising 0.5% of all neuroendocrine cancers and about 2% of gallbladder cancers. Interestingly, those neoplasms can also be observed along with other malignant components of epithelial origin, mostly adenocarcinomas. Herein we report an unusual case of a patient with a gallbladder neoplasm composed of a neuroendocrine carcinoma, a squamous cell carcinoma, and an adenocarcinoma. Methods The patient was a 62-year-old woman who presented with right upper quadrant abdominal pain with a positive Murphy’s sign on physical examination. She was clinically diagnosed with acute cholecystitis and underwent cholecystectomy. Gross examination showed a 5-cm exophytic mass at the gallbladder fundus. Histopathologic examination of the mass showed an infiltrating squamous cell carcinoma and an adjacent high-grade neuroendocrine carcinoma; each of these two components composed more than 30% of the neoplasm and infiltrated into the perimuscular connective tissue with no serosal involvement. Additionally, a superficial adenocarcinoma component was also seen composing 10% of the neoplasm. The squamous cell carcinoma showed moderate differentiation with areas of keratinization; it was positive for Ck7, p40, and p63. The neuroendocrine carcinoma showed areas of geographic necrosis, and the cells had inconspicuous nucleoli and granular chromatin, with numerous mitotic figures; it was positive for synaptophysin and chromogranin. The adenocarcinoma showed gland formation with mucicarmine stain, highlighting the mucin within the neoplastic cells; it was positive for Ck7 but negative for p40. Subsequently, the patient underwent resection of the liver bed, which was negative for metastasis, and was then referred for chemotherapy. Conclusion Our review of the literature revealed seven documented cases of three-component gallbladder neuroendocrine neoplasms. Generally, patients with these tumors have a poor prognosis, and due to their rarity, no specific treatment guidelines have yet been established. It has been suggested that a multipotent common stem cell is the origin of these tumors.
    Type of Medium: Online Resource
    ISSN: 0002-9173 , 1943-7722
    RVK:
    RVK:
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
    detail.hit.zdb_id: 2039921-2
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  • 4
    Online Resource
    Online Resource
    Hindawi Limited ; 2018
    In:  Case Reports in Rheumatology Vol. 2018 ( 2018-10-11), p. 1-5
    In: Case Reports in Rheumatology, Hindawi Limited, Vol. 2018 ( 2018-10-11), p. 1-5
    Abstract: Multiple myeloma (MM) is a malignant plasma cell proliferation producing large numbers of monoclonal immunoglobulins. Typical MM symptoms include anemia, renal failure, hypercalcemia, and bone pain. Atypical symptoms have rarely been reported in the literature. We report a case of a 58-year-old male who presented with symmetrical inflammatory polyarthritis and was misdiagnosed with seronegative rheumatoid arthritis (RA). After failing many RA treatments and with further workup, the diagnosis of MM was made. This rare manifestation of MM carries a diagnostic challenge and causes a significant delay in treating such patients. Here, we report this unusual initial presentation with review of several cases in the English literature describing similar presentations.
    Type of Medium: Online Resource
    ISSN: 2090-6889 , 2090-6897
    Language: English
    Publisher: Hindawi Limited
    Publication Date: 2018
    detail.hit.zdb_id: 2666708-3
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  • 5
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. LB115-LB115
    Abstract: Resistance to cyclin D-cdk4/6 inhibitors (CDK4/6i) represents an unmet clinical need and is frequently caused by compensatory CDK2 activity. Here we describe a novel strategy to prevent CDK4i resistance by using a therapeutic liposomal:peptide formulation, NP-ALT, to inhibit the tyrosine phosphorylation of p27Kip1(CDKN1B), which in turn inhibits both CDK4/6 and CDK2. We find that NP-ALT blocks proliferation in HR+ breast cancer (BC) cells, as well as CDK4i-resistant cell types, including Triple Negative (TN) BC. The peptide ALT is not as stable in primary mammary epithelium, suggesting that NP-ALT has little effect in non-tumor tissues. In HR+ BC cells specifically, NP-ALT treatment induces ROS and RIPK1-dependent necroptosis. Estrogen signaling and ERα appear required. Significantly, NP-ALT induces necroptosis in MCR7 ESRY537S cells, which contain an ER gain of function mutation frequently detected in metastatic patients, which renders them resistant to endocrine therapy. Here we show that NP-ALT causes necroptosis and tumor regression in treatment naïve, palbociclib-resistant and endocrine-resistant BC cells and xenograft models, demonstrating that p27 is a viable therapeutic target to combat drug resistance. Because the RAS/MAPK axis is the target of many therapies, NP-ALT, with its ability to target p27, can deal with the backend drug resistance seen in the presence of other inhibitors, extending the addressable market of this line of therapy. Citation Format: Stacy Wister Blain, Irina Jilishitz, Jason L. Quinones, Priyank Patel, Grace Chen, Jared Pavetsky, Allison VanInwegen VanInwegen, Scott Schoninger, Manasi P. Jogalekar, Vladislav Tsiperson, Lingyue Yan, Yun Wu, Susan R. Gottesman, Jonathan Somma. Blocking p27Kip1phosphorylation with a liposomal:peptide drug induces Reactive Oxygen Species,necroptosis and tumor regression in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB115.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 6
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2020
    In:  Molecular Cancer Therapeutics Vol. 19, No. 1 ( 2020-01-01), p. 3-12
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 19, No. 1 ( 2020-01-01), p. 3-12
    Abstract: CDK4 inhibitors (CDK4/6i), such as palbociclib, ribociclib, and abemaciclib, are approved in combination with hormonal therapy as a front-line treatment for metastatic HR+, HER2- breast cancer. Their targets, CDK4 and CDK6, are cell-cycle regulatory proteins governing the G1–S phase transition across many tissue types. A key challenge remains to uncover biomarkers to identify those patients that may benefit from this class of drugs. Although CDK4/6i addition to estrogen modulation therapy essentially doubles the median progression-free survival, overall survival is not significantly increased. However, in reality only a subset of treated patients respond. Many patients exhibit primary resistance to CDK4/6 inhibition and do not derive any benefit from these agents, often switching to chemotherapy within 6 months. Some patients initially benefit from treatment, but later develop secondary resistance. This highlights the need for complementary or companion diagnostics to pinpoint patients who would respond. In addition, because CDK4 is a bona fide target in other tumor types where CDK4/6i therapy is currently in clinical trials, the lack of target identification may obscure benefit to a subset of patients there as well. This review summarizes the current status of CDK4/6i biomarker test development, both in clinical trials and at the bench, with particular attention paid to those which have a strong biological basis as well as supportive clinical data.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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