Current combination antiretroviral therapies (cART) efficiently suppress HIV-1 reproduction in humans, but the virus persists as integrated proviral reservoirs in small numbers of cells. To generate an antiviral agent capable of eradicating the provirus from infected cells, we employed 145 cycles of substrate-linked directed evolution to evolve a recombinase (Brec1) that site-specifically recognizes a 34-bp sequence present in the long terminal repeats (LTRs) of the majority of the clinically relevant HIV-1 strains and subtypes. Brec1 efficiently, precisely and safely removes the integrated provirus from infected cells and is efficacious on clinical HIV-1 isolates in vitro and in vivo, including in mice humanized with patient-derived cells. Our data suggest that Brec1 has potential for clinical application as a curative HIV-1 therapy.
This first large randomized trial suggests high efficacy and excellent tolerability of a neoadjuvant nab-paclitaxel/carboplatin regimen, superior to nab-paclitaxel/gemcitabine in TNBC. De-escalation of further chemotherapy in patients with early pCR after a short anthracycline-free regimen is a promising field of future research. Early necrotic morphological changes and/or proliferation decrease after the first therapy cycle seem to be associated with subsequent pCR.
<b><i>Background:</i></b> Desmoid type fibromatoses has proven to be a diagnostic and therapeutic challenge, as they often appear primarily as a carcinoma of the breast with a high recurrence risk. <b><i>Patients:</i></b> A digital archive search was performed for the period from 2009 to the end of 2018. Inclusion criteria consisted of histological examination of at least the surgical specimen in the reference pathology department and at least a second opinion diagnosis in the reference radiology department. <b><i>Results:</i></b> A total of 14 women and 1 man underwent surgery on desmoid type fibromatosis<b><i></i></b>of the breast. The average patient age was 49 years (range: 22–72 years). The mean tumor size was 2.2 cm (range: 0.8–4.2 cm). The tumor was detectable in mammography in 12 out of 13 patients and in all 15 patients in sonography. MRI was performed preoperatively in 6 patients; in all of the patients, the tumor was visualized with inhomogeneous contrast enhancement. In the imaging procedures, all desmoid type fibromatoses were classified as suspicious. Performing the core biopsy, preoperative histology confirmed desmoid fibromatosis in 12 out of 15 patients. Nuclear stain for ß-catenin was positive in 7 out of 10 patients.<b><i></i></b>Negative staining was found for AE1/A3 in 10 out of 10 and CD34 in 12 out of 12 patients. In all of the patients, a single-stage operation without the detection of border-forming tumor margins was performed. The follow-up interval ranged from 16 to 96 months (mean: 44.86 months, median: 43 months). In this follow-up period, no patient was diagnosed with desmoid tumor recurrence. <b><i>Conclusion:</i></b> In imaging, desmoid type fibromatosis of the breast has typical malignancy-related criteria. Extensive preoperative diagnostics enable the planning of complete primary excision of the lesion and reduce the recurrence risk.
BackgroundCarbonic anhydrase IX (CAIX) is a membranous expressed metalloenzyme involved in pH homeostasis and cell adhesion. The protein is overexpressed in a variety of tumors and potentially associated with negative outcome. This study was designed to investigate the prognostic role of CAIX in serum and tumor tissue of patients with primary cervical cancer.MethodsTumor samples of 221 consecutive patients with primary cervical cancer who underwent surgery between 1993 and 2008 were analyzed for CAIX expression by immunohistochemistry. Additionally, preoperative serum CAIX concentrations were determined by ELISA in a subset of patients. Correlation with intratumoral CAIX expression as well as clinicopathological factors and outcome was analyzed.ResultsCAIX expression was observed in 81.9% of the tumor specimens; 62.0% showed a moderate or strong staining intensity. Moderate/strong expression was associated with squamous histology (p = 0.024), advanced tumor stage (p = 0.001), greater invasion depth (p = 0.025), undifferentiated tumor grade (p < 0.001) and high preoperative SCC-Ag values (p = 0.042). Furthermore patients with moderate/strong intratumoral CAIX expression had a higher number of metastatic lymph nodes compared to those with none/weak intratumoral expression levels (p = 0.047) and there was a non-significant association between high intratumoral CAIX expression and shorter survival (p = 0.118). Preoperative serum concentrations of CAIX ranged between 23 and 499 pg/mL and did not correlate with intratumoral expression or other clinicopathological variables.ConclusionCAIX is associated with advanced tumor stages and lymph node metastases in cervical cancer, potentially representing a new target in this disease. In contrast to other epithelial cancers we could not observe a correlation between serum CAIX and its intratumoral expression.
Stable integration of HIV proviral DNA into host cell chromosomes, a hallmark and essential feature of the retroviral life cycle, establishes the infection permanently. Current antiretroviral combination drug therapy cannot cure HIV infection. However, expressing an engineered HIV-1 long terminal repeat (LTR) site-specific recombinase (Tre), shown to excise integrated proviral DNA in vitro, may provide a novel and highly promising antiviral strategy. We report here the conditional expression of Tre-recombinase from an advanced lentiviral self-inactivation (SIN) vector in HIV-infected cells. We demonstrate faithful transgene expression, resulting in accurate provirus excision in the absence of cytopathic effects. Moreover, pronounced Tre-mediated antiviral effects are demonstrated in vivo, particularly in humanized Rag2−/−γc−/− mice engrafted with either Tre-transduced primary CD4+ T cells, or Tre-transduced CD34+ hematopoietic stem and progenitor cells (HSC). Taken together, our data support the use of Tre-recombinase in novel therapy strategies aiming to provide a cure for HIV.
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