Circumvention of multidrug resistance by a quinoline derivative, MS-209, in multidrug-resistant human small-cell lung cancer cells and its synergistic interaction with cyclosporin A or verapamil

Purpose and methods: To develop a clinically useful approach to circumvent P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) in MDR human small-cell lung cancer (SCLC), we examined the ability of a novel quinoline compound, MS-209, to reverse MDR by inhibition of P-gp function in combination with other MDR-reversing drugs using a cytotoxicity assay. Results: We established MDR human SCLC cells by culture in medium with gradually increasing concentrations of adriamycin (ADM). Compared with the parental human SCLC cells, SBC-3, the MDR variant SBC-3 cells obtained (SBC-3/ADM) were highly resistant to various chemotherapeutic agents due to P-gp expression. MS-209 reversed the resistance to ADM and vincristine (VCR) of SBC-3/ADM and H69/VP cells in a dose-dependent manner. Moreover, MS-209 in combination with cyclosporin A (CsA) or verapamil (VER) synergistically enhanced the antitumor effects of ADM and VCR on SBC-3/ADM cells. MS-209 restored ADM incorporation and this effect was enhanced by CsA and VER, suggesting that these synergistic effects were due to competitive inhibition of P-gp function. Conclusion: MS-209 in combination with CsA or VER might increase the efficacy of these chemotherapeutic agents against MDR human SCLC cells. Received: 10 December 1997 / Accepted: 16 April 1998     

Dendritic cell-based immunotherapy of malignant gliomas

The failure of conventional treatment modalities for gliomas, in spite of tremendous progress in research in the past two decades, has led to increasing interest in alternative treatment strategies, including immunotherapy. It has become evident that vaccination with dendritic cells (DC), designed to express tumor antigens, is a potent strategy to elicit anti-tumor immune response in both pre-clinical and clinical settings. Various methods have been applied in order to induce DC to express tumor antigens including: pulsing with isolated tumor peptides or whole tumor lysate; fusion with tumor cells; and pulsing with apoptotic tumor cells. Herein, we review the recent progress in DC biology with regard to tumor immunity and discuss current DC-based strategies and future prospects in immunotherapy for malignant gliomas.     

Humanized anti-ganglioside GM2 antibody is effective to induce antibody-dependent cell-mediated cytotoxicity in mononuclear cells from lung cancer patients

Ganglioside GM2 is one of the major gangliosides expressed on the cell surface of human tumors including lung cancer. We have previously reported that a mouse-human chimeric monoclonal antibody (mAb), KM966, against GM2 promotes the lysis of lung cancer cells by human blood mononuclear cells (MNC) of healthy donors. In this study, we examined antibody-dependent cell-mediated cytotoxicity (ADCC) of MNC, using KM966 mAb and its humanized counterpart, KM8969, in 16 lung cancer patients and 18 control patients. The ADCC activity was assessed by 4-h (51)Cr release from GM2 positive SBC-3 small cell lung cancer cells. MNC from lung cancer patients exhibited similar ADCC activity to those from control patients when KM966 and KM8969 were used as mAb. Moreover, effective ADCC activity was observed even in MNC from advanced lung cancer patients. These observations suggest the potential activity of humanized anti-GM2 mAb (KM8969), as well as chimeric KM966, in biological therapy for lung cancer patients.     

Prevalence and associated risk factors of Giardia duodenalis infection among school-going children in Nepal

Parasitology Research - This study aimed to determine the prevalence of intestinal parasites and its associated risk factors among school-going children in Kathmandu, Nepal. Between August and...     

Concurrent biopsies of both grafts in recipients of simultaneous pancreas and kidney demonstrate high rates of discordance for rejection as well as discordance in type of rejection – a retrospective study

It is commonly assumed that in simultaneous pancreas and kidney (SPK) recipients, rejection of the two organs is concordant. As a result, concurrent biopsies of both organs are rarely performed and there are limited histological data on how often rejection is in fact discordant. We reviewed all SPK recipients transplanted at the University of Wisconsin between January 01, 2001, and December 31, 2016, that underwent biopsy of both organs. We included all patients whose biopsies were within 30 days. If patients were treated for rejection between biopsies, they were excluded if the biopsies were more than 4 days apart. Ninety‐one simultaneous biopsies were performed within 30 days of each other, and 40 met our inclusion criteria. A total of 25 (62.5%) patients had concordance of biopsy findings: 11 had rejection of both organs, and 14 had no rejection of either organ. The other 15 (37.5%) were discordant for rejection, with 10 having pancreas‐only rejection and five kidney‐only rejection. It was striking to find that four of the 11 patients with concordance for rejection (36%) had different types (AMR, ACR, or mixed) of rejection in the two organs. This large series of simultaneous pancreas and kidney biopsies demonstrates the continued utility of performing biopsies of both organs.     

Infiltrating CD11b+CD11c+ cells have the potential to mediate inducible nitric oxide synthase‐dependent cell death in mammary carcinomas of HER‐2/neu transgenic mice

The development of autochtonous mammary tumors in HER‐2/neu transgenic mice is facilitated by immune tolerance to the neu‐transgene. However, appropriate vaccination strategies can initiate immune system‐mediated antitumor response by a process that requires IFN‐γ. We investigated the role of inducible nitric oxide synthase (iNOS) induction by IFN‐γ to promote tumor cell apoptosis. Tumors from FVBN202 mice expressing the normal neu gene under the control of the MMTV‐LTR were treated in slice cultures with IFN‐γ for up to 24 hr. Apoptosis was induced, which depended on iNOS enzymatic activity. iNOS expression was predominantly found in infiltrating CD11b⁺CD11c⁺ myeloid cells and at much lower levels in the tumor epithelium. By contrast, IFN‐γ treatment of explant cultures of tumor epithelial cells was not sufficient to efficiently induce iNOS, emphasizing an important role of the integrity of tumor tissue architecture, which was preserved in the slice cultures. This notion was further supported by the upregulation of iNOS costimulatory cytokines TNF‐α and IL‐1β in slice cultures but not in explants and the capability of purified CD11b⁺CD11c⁺ cells to enhance iNOS expression of tumor cells in cocultures. The findings suggest that tumor‐infiltrating myeloid cells in immuno‐tolerant HER‐2/neu transgenic mice possess tumor killing ability via induction of iNOS and underline the capacity of antitumor strategies designed to stimulate infiltrating myeloid cells.     

Immunization with wild-type p53 gene sequences coadministered with Flt3 ligand induces an antigen-specific type 1 T-cell response.

We examined the ability of immunization with sequential adenovirus/plasmid DNA vectors expressing human wild-type p53 to stimulate a type 1 T-cell response and induce protection against challenge from a metastatic tumor that expresses mutated murine p53. We found that tumor protection and an antigen (Ag)-specific immune response were enhanced by prior injection of Flt3 ligand (Flt3L) at a dose and schedule that significantly increased dendritic cell (DC) number and frequency. Preliminary studies using enzyme-linked immunospot and Winn assays suggested that Ag-specific CD8 cells, with their significant increase in IFN-gamma-secreting activity (Tc1 cells), were responsible for the tumor protection. The delayed-type hypersensitivity response to p53 was increased in mice immunized with p53 alone or p53 and Flt3L compared with a negative control. In contrast, spleen cells from mice immunized with p53 and Flt3L exhibited a higher Ag-specific proliferative response than mice immunized with p53 alone. The frequencies of Ag-specific IFN-gamma and interleukin (IL)-4-secreting cells were determined using an enzyme-linked immunospot assay, which demonstrated that the frequency of IFN-gamma-secreting cells was significantly higher in mice immunized with p53 and Flt3L than in mice receiving Flt3L, excipient, or p53 treatment alone. In contrast, the frequency of IL-4-secreting cells did not differ significantly among these groups. We also observed an increased frequency of IL-12 and IFN-gamma-secreting cells (but not IL-4 or IL-10) in the spleens of mice immediately after 10 days of Flt3L treatment, which was also the day of p53 priming. This observation supports the likelihood that there are multiple mechanisms of Flt3L adjuvant activity, including expansion of DC and type 1 T-cell number. Overall, these results suggest that immunization with p53 genetic sequences after in vivo expansion of DC, using Flt3L, provides a useful strategy to induce p53-specific, and protective, type 1 T-cell responses.     

Impacts and challenges of United States medical students during the COVID-19 pandemic

The delivery of medical student education has changed rapidly during the coronavirus disease 2019 (COVID-19) pandemic. Students in their pre-clinical years have transitioned to online courses and examinations. Students in their clinical years are not permitted on clinical rotations, and face uncertainties in career exploration and the residency application process. Medical students in all stages of training are volunteering and helping their communities. The future presence of COVID-19 throughout the United States is unknown, and medical students are eager to return to their training. This paper outlines current challenges in medical student education and the various responses that have been adopted. We also discuss possible future directions for students through involvement in telemedicine, outpatient clinic visits, and non-respiratory inpatient care tasks as adequate personal protective equipment, COVID-19 testing, and resources become more widely available.     

Utility of post-urinary tract infection imaging in patients with normal prenatal renal ultrasound

The American Academy of Pediatrics recommends renal ultrasound (RUS) and voiding cystourethrography (VCUG) for all infants after a first urinary tract infection (UTI). However, many congenital renal anomalies are identified by a prenatal US. At the present time, there are no data regarding the yield of post-UTI imaging among infants who have a documented normal prenatal US. We retrospectively reviewed the charts of all patients <1 year of age with a first UTI who had normal kidneys noted on prenatal US to determine the frequency of abnormal findings. Abnormal RUS and VCUG results were noted in 5.1% (24 of 471) and 20.4% (75 of 368) of infants, respectively. While the abnormal US rate is significantly less than what has been previously reported, the frequency of abnormal VCUGs is similar. These results suggest that a post-UTI RUS may not be needed if the prenatal US was normal. However, a VCUG continues to be indicated.