Retracted: Allogeneic Natural Killer and Cytomegalovirus (CMV)-pp65 Pulsed Dendritic Cells Induced Complete Response Through 15 Months in a Patient with Recurrent Glioblastoma: A Case Study.

Retraction Notice: The manuscript contains inaccurate regulatory details about the treatment used in this case. Reference: Serhat Gumrukcu, Tung X. Nguyen, Rachel L. White, Gregory T. Howell, Phillip Musikanth. Allogeneic Natural Killer and Cytomegalovirus (CMV)-pp65 Pulsed Dendritic Cells Induced Complete Response Through 15 Months in a Patient with Recurrent Glioblastoma: A Case Study. Am J Case Rep. 2021; 22: e931030. DOI: 10.12659/AJCR.931030.

Inability of ovarian cancers to upregulate their MHC-class I surface expression marks their aggressiveness and increased susceptibility to NK cell-mediated cytotoxicity.

We extended our previous observations with other tumor models to study seven ovarian tumor cell lines-OVCAR3, OVCAR4, OVCAR8, SKOV3, Kuramochi, OAW28, and CaOV3. We found that NK cells targeted and killed poorly differentiated OVCAR8 and CAOV3; these two tumor lines express lower MHC-class I and higher CD44 surface receptors. OVCAR3 and OVCAR4 were more resistant to NK cell-mediated cytotoxicity, and SKOV3, Kuramochi and OAW28 had intermediate sensitivity to NK cell-mediated cytotoxicity, likely representing well-differentiated and moderately differentiated ovarian tumor cell lines, respectively. Similar trends were observed for secretion of IFN-γ by the NK cells when co-cultured with different ovarian tumor cell lines. Treatment with both IFN-γ and TNF-α upregulated MHC-class I in all ovarian tumor cell lines and resulted in tumor resistance to NK cell-mediated cytotoxicity and decreased secretion of IFN-γ in co-cultures of NK cells with tumors cells with the exception of OVCAR8 and CAOV3 which did not upregulate MHC-class I and remained sensitive to NK cell-mediated cytotoxicity and increased secretion of IFN-γ when co-cultured with NK cells. Similarly, treatment with NK cell supernatants induced resistance to NK cell-mediated cytotoxicity in OVCAR4 but not in OVCAR8, and the resistance to killing was correlated with the increased surface expression of MHC-class I in OVCAR4 but not in OVCAR8. In addition, OVCAR4 was found to be carboplatin sensitive before and after treatment with IFN-γ and NK cell supernatants, whereas OVCAR8 remained carboplatin resistant with and without treatment with IFN-γ and NK cell supernatants. Overall, sensitivity to NK cell-mediated killing correlated with the levels of tumor differentiation and aggressiveness, and more importantly, poorly differentiated ovarian tumors were unable to upregulate MHC-class I under the activating conditions for MHC-class I, a feature that was not seen in other tumor models and may likely be specific to ovarian tumors. Such tumors may also pose a significant challenge in elimination by the T cells; however, NK cells are capable of targeting such tumors and can be exploited to eliminate these tumors in immunotherapeutic strategies.

Zoledronic acid mediated differential activation of NK cells in different organs of WT and Rag2-/- mice; stark differences between the bone marrow and gingivae.

We have previously shown that natural killer (NK) cells expand, and increase their function after interaction with cells that exhibit a number of different knock-down genes. We hypothesized that deletion or knockdown of a variety of key genes such as RAG may cause de-differentiation of the cells which could lead to increased NK expansion and function since we have shown previously that NK cells are activated and expanded by less differentiated cells. When comparing the function of NK cells from bone marrow (BM), spleen, pancreas, adipose tissue, and gingiva from WT mice to those from Rag2-/- mice, we observed a significant increase in IFN-γ secretion in all tissues of Rag2-/- mice versus in WT mice, with the exception of the gingivae in which similar levels were observed. After injecting WT mice with zoledronic acid (ZOL) and tooth extraction, immune cells from BM, spleen, and purified NK cells from spleen exhibited very high induction of IFN-γ and NK cell-mediated cytotoxicity with the exception of gingiva in which immune cells exhibited the opposite. In Rag2-/- mice, ZOL injection and tooth extraction stimulated IFN-γ secretion from BM immune cells but inhibited IFN-γ secretion from both spleen and gingivae. In both WT and Rag2-/- mice, immune cells from gingivae exhibited decreased IFN-γ secretion when activated, indicating significant regulation of immune cell function in the gingival microenvironment. However, even though significantly lower induction of IFN-γ was observed in both WT and Rag2-/- gingival cells after ZOL injection, ZOL mediated secretion of IFN-γ was still higher in the gingivae of WT mice when compared to those of Rag2-/- gingival cells. These results suggest an important role for IFN-γ in the pathogenesis of osteonecrosis lesions observed in post-tooth extraction jawbone.

A Clinically Validated, Broadly Active, Oral Viral Superinfection Therapy Could Mitigate Symptoms in Early-stage COVID-19 Patients.

More than 200 viruses infect humans, but treatments are available for less than ten of them. To narrow the gap between 'bugs and drugs,' a paradigm shift is required. The "one drug, one bug" approach can be expanded to a "one drug, multiple bugs" strategy such that the host's defense system is targeted rather than the virus. Viral superinfection therapy (SIT) activates interferon genes' natural, antiviral defense system of host cells following exposure to viral infection, e.g., superinfection with an attenuated infectious bursal disease virus (IBDV) with the release of its double-stranded RNA (dsRNA) cargo inside host cells. An attenuated IBDV therapeutic vaccine has successfully treated hepatitis A virus infection (HAV) in marmoset monkeys as well as acute hepatitis B and hepatitis C virus infections (HBV/HCV) in 42 patients. SIT has also been shown to be safe and effective in four patients with chronic HBV or HCV infection with hepatic decompensation. The proof-of-principle of SIT has also been demonstrated in a 43-year-old male patient with COVID-19. Three doses of orally administered IBDV (3x106 IU) alleviated most of his COVID-19 symptoms; even his sense of smell returned within a week. Two additional COVID-19 patients responded similarly to oral treatment with IBDV. Furthermore, a severe herpes zoster ophthalmicus outbreak with orbital edema responded to a combination of acyclovir and 7 doses of IBDV (7x106 IU) within a few days. IBDV is simple to manufacture and affordable, even in resource-limited settings. Acid-resistant IBDV can be orally administered in an outpatient setting, providing simple dosing and high medication adherence. Under an Emergency Use Authorization, the broad-spectrum IBDV drug candidate could be tested immediately in clinical trials and rapidly distributed to millions of early-stage patients with COVID-19. The German Paul Ehrlich Institute is currently supporting a phase I safety study for persons acutely infected with SARS­CoV-2. An expert team of the US National Institutes of Health-sponsored ACTIV public-private partnership came to the conclusion that the IBDV drug candidate shows merit as a potential treatment for COVID19, and an FDA-approved clinical trial is in the pipelines in Los Angeles.

Allogeneic Natural Killer and Cytomegalovirus (CMV)-pp65 Pulsed Dendritic Cells Induced Complete Response Through 15 Months in a Patient with Recurrent Glioblastoma: A Case Study.

BACKGROUND Glioblastoma (GBM) is a highly aggressive brain tumor with poor survival outcomes. While conventional treatment strategies such as surgery, radiation, and chemotherapy can extend survival, the prognosis for GBM patients after 2 years remains low. One-year progression-free survival (PFS) and complete response (CR) with recurrent GBM is extremely low. Recent clinical trials using either engineered chimeric antigen receptor (CAR) T cells, autologous dendritic cell (DC) vaccination, or natural killer (NK) cells have shown promise for patients with GBM following initial diagnosis. Despite these significant immunotherapeutic advancements, new strategies need to be developed to address the poor survival outcomes for GBM. CASE REPORT A 36-year-old male patient with recurrent bilateral parietal GBM, following subtotal resection, was treated using an immunotherapeutic strategy combining lymphosuppressive conditioning with intravenous administration of highly purified allogeneic NK cells (mismatched for inhibitory killer Ig-like receptor [KIR]-human leukocyte antigen [HLA] ligand interactions), celecoxib, temozolomide (TMZ), tetanus-diphtheria vaccination, and multiple intradermal injections of human cytomegalovirus (CMV)-pp65 pulsed dendritic cells. This treatment did not exhibit any toxic effects and resulted in regression of intracranial residual disease on both hemispheres. Additionally, the clinical response was durable, persisting for more than 15 months after the first infusion of KIR-HLA-mismatched purified allogenic NK cells. CONCLUSIONS A patient with recurrent GBM achieved durable CR with a novel treatment strategy with allogeneic NK cells and DC pulsed with CMV-pp65 following subtotal surgical resection. If confirmed in additional patients, this combination approach could offer an effective therapeutic option for people with an otherwise dismal prognosis.

Red flag in the emergency department: fracture and primary failure of a prosthetic valve.

This case report concerns a patient with fracture and primary dysfunction of a prosthetic valve. A 40-year-old man presented to the Emergency Department with a chief complaint of breakthrough pleuritic back pain and shortness of breath. Past surgical history was significant only for an aortic valve replacement and mitral valve replacement performed 16 years prior. The transthoracic echocardiography raised suspicion of prosthesis malposition. The patient was taken to the operating room by cardiothoracic surgeons for valve replacement. Operative findings revealed that a prosthetic valve leaflet in the mitral position had broken off. Primary prosthetic valve failure should not be overlooked in the differential diagnosis of patients with valve replacement and a rapidly deteriorating clinical course. Emergency echocardiography is a guide to convenient diagnosis and management. Early surgical consultation and early reparative surgery might prevent unnecessary morbidity and mortality.

Acute coronary ischemia following centipede envenomation: case report and review of the literature.

This is the first known case report of electrocardiographic (ECG) changes suggestive of coronary vasospasm following a centipede envenomation. A 60-year-old man presented to the emergency department (ED) 1 hour after being stung by a 12-cm centipede. He complained of right great toe pain that did not radiate to his leg. The patient had no known ischemic heart disease. He did not describe any exertional symptoms but admitted experiencing weakness. During the ED course, concurrent with obtaining peripheral intravenous access, the patient experienced diaphoresis, dizziness, hypotension, and bradycardia. His ECG showed new ST-T wave changes, which suggested an acute ischemic process. The patient's blood pressure was 89/60 mm Hg, his pulse rate was 47 beats/min, and his respiration rate was 28 breaths/min. In the following hours, ECG findings returned to baseline. His blood pressure improved gradually with fluid resuscitation after approximately 5 hours. Cardiac markers returned to normal in the 13th hour after the event, and the patient underwent exercise stress testing, which was negative. The patient was discharged with cardiology follow-up. Adult patients with centipede envenomation should be closely monitored in anticipation of possible myocardial ischemia due to vasospasm, hypotension, and myocardial toxic effects of the venom. A child receiving the same amount of venom would be potentially at greater risk.