Simple virus-free mouse models of COVID-19 pathologies and oral therapeutic intervention.

The paucity of preclinical models that recapitulate COVID-19 pathology without requiring SARS-COV-2 adaptation and humanized/transgenic mice limits research into new therapeutics against the frequently emerging variants-of-concern. We developed virus-free models by C57BL/6 mice receiving oropharyngeal instillations of a SARS-COV-2 ribo-oligonucleotide common in all variants or specific to Delta/Omicron variants, concurrently with low-dose bleomycin. Mice developed COVID-19-like lung pathologies including ground-glass opacities, interstitial fibrosis, congested alveoli, and became moribund. Lung tissues from these mice and bronchoalveolar lavage and lung tissues from patients with COVID-19 showed elevated levels of hyaluronic acid (HA), HA-family members, an inflammatory signature, and immune cell infiltration. 4-methylumbelliferone (4-MU), an oral drug for biliary-spasm treatment, inhibits HA-synthesis. At the human equivalent dose, 4-MU prevented/inhibited COVID-19-like pathologies and long-term morbidity; 4-MU and metabolites accumulated in mice lungs. Therefore, these versatile SARS-COV-2 ribo-oligonucleotide oropharyngeal models recapitulate COVID-19 pathology, with HA as its critical mediator and 4-MU as a potential therapeutic for COVID-19.

The landscape of penile cancer research in Germany and Austria: a survey among professors in academic centers holding chair positions and results of a literature search.

BACKGROUND: Research on penile cancer (PeCa) is predominantly conducted in countries with centralized treatment of PeCa-patients. In Germany and Austria (G + A), no state-regulated centralization is established, and no information is available on how PeCa-research is organized. METHODS: Current research competence in PeCa was assessed by a 36-item questionnaire sent to all chairholders of urological academic centers in G + A. Based on PubMed records, all scientific PeCa-articles of 2012-2022 from G + A were identified. Current research trends were assessed by dividing the literature search into two periods (P1: 2012-2017, P2: 2018-2022). A bibliometric analysis was supplemented. RESULTS: Response rate of the questionnaire was 75%, a median of 13 (IQR: 9-26) PeCa-patients/center was observed in 2021. Retrospective case series were conducted by 38.9% of participating clinics, while involvement in randomized-controlled trials was stated in 8.3% and in basic/fundamental research in 19.4%. 77.8% declared an interest in future multicenter projects. 205 PeCa-articles were identified [median impact factor: 2.77 (IQR: 0.90-4.37)]. Compared to P1, P2 showed a significant increase in the median annual publication count (29 (IQR: 13-17) vs. 15 (IQR: 19-29), p < 0.001), in multicenter studies (79.1% vs. 63.6%, p = 0.018), and in multinational studies (53% vs. 28.9%, p < 0.001); the proportion of basic/fundamental research articles significantly declined (16.5% vs. 28.9%, p = 0.041). Four of the top-5 institutions publishing PeCa-articles are academic centers. Bibliometric analyses revealed author networks, primary research areas in PeCa, and dominant journals for publications. CONCLUSIONS: Given the lack of centralization in G + A, this analysis highlights the need for research coordination within multicenter PeCa-projects. The decline in basic/fundamental research should be effectively addressed by the allocation of funded research projects.

Centralizing Penile Cancer Care in Germany and Austria: Just a Dream or a Fast-Approaching Reality? Results of a Survey Study among Urological Department Chairs and Modeling of Real Treatment Numbers of Penile Cancer Patients.

INTRODUCTION: In countries characterized by a centralization of therapy management, patients with penile cancer (PeCa) have shown improvements in guideline adherence and ultimately, improved carcinoma-specific survival. Germany and Austria (G + A) have no state-regulated centralization of PeCa management, and the perspectives of urological university department chairs (UUDCs) in these countries, who act as drivers of professional and political developments, on this topic are currently unknown. METHODS: Surveys containing 36 response options, including specific questions regarding perspectives on PeCa centralization, were sent to the 48 UUDC in G + A in January 2023. In addition to analyzing the responses, closely following the CROSS checklist, a modeling of the real healthcare situation of in-house PeCa patients in G + A was conducted. RESULTS: The response rate was 75% (36/48). 94% and 89% of the UUDCs considered PeCa centralization meaningful and feasible in the medium term, respectively. Among the UUDCs, 72% estimated centralization within university hospitals as appropriate, while 28% favored a geographically oriented approach. Additionally, 97% of the UUDCs emphasized the importance of bridging the gap until implementation of centralization by establishing PeCa second-opinion portals. No country-specific differences were observed. The median number of in-house PeCa cases at the university hospitals in G + A was 13 (interquartile range: 9-26). A significant positive correlation was observed between the annual number of in-house PeCa cases at a given university hospital and the perspective of the UUDCs that centralization as meaningful by its UUDC (0.024). Under assumptions permissible for modeling, the average number of in-house PeCa cases in academic hospitals in G + A was approximately 30 times higher than in nonacademic hospitals. CONCLUSION: This study provides the first data on the perspectives of UUDCs in G + A concerning centralization of PeCa therapy management. Even without state-regulated centralization in G + A, there is currently a clear focusing of PeCa treatments in university hospitals. Further necessary steps toward a structured PeCa centralization are discussed in this manuscript.

[Are there any volume-related effects on treatment options for patients with penile cancer? Results of a survey among university hospitals in Germany and Austria]. / Gibt es fallzahlabhängige Effekte auf Behandlungsangebote für Patienten mit einem Peniskarzinom? Ergebnisse einer Umfrage an Universitätsklinika in Deutschland und Österreich.

BACKGROUND: Currently, 959 men in Germany and 67 in Austria are diagnosed with penile cancer each year, with an increase of approximately 20% in the last decade [RKI 2021, Statcube.at 2023]. Despite the rising incidence, the number of cases per hospital remains low. The median annual number of penile cancer cases at university hospitals in the DACH region was 7 patients (IQR 5-10) in 2017 [E-PROPS group 2021]. The compromised institutional expertise due to low case numbers is compounded with inadequate adherence to penile cancer guidelines, as shown in several studies. The centralization, which is rigorously implemented in countries such as the UK, enabled a significant increase in organ-preserving primary tumor surgery and stage-adapted lymphadenectomies, as well as improved patient survival in cases of penile cancer, resulting in a claim for a similar centralization in Germany and Austria. The aim of this study was to determine the current effects of case volume on penile cancer related treatment options at university hospitals in Germany and Austria. MATERIALS AND METHODS: In January 2023, a survey was sent to the heads of 48 urological university hospitals in Germany and Austria, including questions regarding case volume in 2021 (total number of inpatient and penile cancer cases), treatment options for primary tumors and inguinal lymphadenectomy (ILAE), the availability of a designated penile cancer surgeon, and the professional responsibility for systemic therapies in penile cancer. Correlations and differences related to case volume were statistically analyzed without adjustments. RESULTS: The response rate was 75% (n=36/48). In total, 626 penile cancer patients were treated at the 36 responding university hospitals in 2021, representing approximately 60% of the expected incidence in Germany and Austria. The annual median total number of cases was 2807 (IQR 1937-3653), and for penile cancer, it was 13 (IQR 9-26). There was no significant correlation between the total inpatient and penile cancer caseloads (p=0.34). The number of organ-preserving therapy procedures for the primary tumor, the availability of modern ILAE procedures, the presence of a designated penile cancer surgeon, and the responsibility for systemic therapies were not significantly influenced by the total inpatient or penile cancer case volume of the treating hospitals, regardless of whether the case volumes were dichotomized at the median or upper quartile. No significant differences between Germany and Austria were observed. CONCLUSION: Despite a significant increase in the annual number of penile cancer cases at university hospitals in Germany and Austria compared to 2017, we found no case volume-related effects on structural quality with respect to penile cancer therapy. In the light of the proven benefits of centralization, we interpret this result as an argument for the necessity of establishing nationally organized penile cancer centers with even higher case volumes compared to the status quo, in light of the proven benefits of centralization.

The alternative renin-angiotensin-system (RAS) signalling pathway in prostate cancer and its link to the current COVID-19 pandemic.

BACKGROUND: The renin-angiotensin system is known to maintain blood pressure and body fluids. However, it has been found to consist of at least two major constituents, the classic and the alternative pathway, balancing and supporting each other's signalling in a very intricate way. Current research has shown that the renin-angiotensin system is involved in a broad range of biological processes and diseases, such as cancer and infectious diseases. METHODS AND RESULTS: We conducted a literature review on the interaction of the renin-angiotensin system and prostate cancer and explored the research on the possible impact of the SARS-CoV-2 virus in this context. This review provides an update on contemporary knowledge into the alternative renin-angiotensin system, its role in cancer, specifically prostate cancer, and the implications of the current COVID-19 pandemic on cancer and cancer care. CONCLUSION: In this work, we aim to demonstrate how shifting the RAS signalling pathway from the classic to the alternative axis seems to be a viable option in supporting treatment of specific cancers and at the same time demonstrating beneficial properties in supportive care. It however seems to be the case that the infection with SARS-CoV-2 and subsequent impairment of the renin-angiotensin-system could exhibit serious deleterious long-term effects even in oncology.

Targeting hyaluronic acid synthase-3 (HAS3) for the treatment of advanced renal cell carcinoma.

BACKGROUND: Hyaluronic acid (HA) promotes cancer metastasis; however, the currently approved treatments do not target HA. Metastatic renal carcinoma (mRCC) is an incurable disease. Sorafenib (SF) is a modestly effective antiangiogenic drug for mRCC. Although only endothelial cells express known SF targets, SF is cytotoxic to RCC cells at concentrations higher than the pharmacological-dose (5-µM). Using patient cohorts, mRCC models, and SF combination with 4-methylumbelliferone (MU), we discovered an SF target in RCC cells and targeted it for treatment. METHODS: We analyzed HA-synthase (HAS1, HAS2, HAS3) expression in RCC cells and clinical (n = 129), TCGA-KIRC (n = 542), and TCGA-KIRP (n = 291) cohorts. We evaluated the efficacy of SF and SF plus MU combination in RCC cells, HAS3-transfectants, endothelial-RCC co-cultures, and xenografts. RESULTS: RCC cells showed increased HAS3 expression. In the clinical and TCGA-KIRC/TCGA-KIRP cohorts, higher HAS3 levels predicted metastasis and shorter survival. At > 10-µM dose, SF inhibited HAS3/HA-synthesis and RCC cell growth. However, at ≤ 5-µM dose SF in combination with MU inhibited HAS3/HA synthesis, growth of RCC cells and endothelial-RCC co-cultures, and induced apoptosis. The combination inhibited motility/invasion and an HA-signaling-related invasive-signature. We previously showed that MU inhibits SF inactivation in RCC cells. While HAS3-knockdown transfectants were sensitive to SF, ectopic-HAS3-expression induced resistance to the combination. In RCC models, the combination inhibited tumor growth and metastasis with little toxicity; however, ectopic-HAS3-expressing tumors were resistant. CONCLUSION: HAS3 is the first known target of SF in RCC cells. In combination with MU (human equivalent-dose, 0.6-1.1-g/day), SF targets HAS3 and effectively abrogates mRCC.

Molecular Oncology of Bladder Cancer from Inception to Modern Perspective.

Within the last forty years, seminal contributions have been made in the areas of bladder cancer (BC) biology, driver genes, molecular profiling, biomarkers, and therapeutic targets for improving personalized patient care. This overview includes seminal discoveries and advances in the molecular oncology of BC. Starting with the concept of divergent molecular pathways for the development of low- and high-grade bladder tumors, field cancerization versus clonality of bladder tumors, cancer driver genes/mutations, genetic polymorphisms, and bacillus Calmette-Guérin (BCG) as an early form of immunotherapy are some of the conceptual contributions towards improving patient care. Although beginning with a promise of predicting prognosis and individualizing treatments, "-omic" approaches and molecular subtypes have revealed the importance of BC stem cells, lineage plasticity, and intra-tumor heterogeneity as the next frontiers for realizing individualized patient care. Along with urine as the optimal non-invasive liquid biopsy, BC is at the forefront of the biomarker field. If the goal is to reduce the number of cystoscopies but not to replace them for monitoring recurrence and asymptomatic microscopic hematuria, a BC marker may reach clinical acceptance. As advances in the molecular oncology of BC continue, the next twenty-five years should significantly advance personalized care for BC patients.

HYAL4-V1/Chondroitinase (Chase) Drives Gemcitabine Resistance and Predicts Chemotherapy Failure in Patients with Bladder Cancer.

PURPOSE: Gemcitabine-based chemotherapy regimens are first-line for several advanced cancers. Because of better tolerability, gemcitabine + cisplatin is a preferred neoadjuvant, adjuvant, and/or palliative chemotherapy regimen for advanced bladder cancer. Nevertheless, predicting treatment failure and overcoming resistance remain unmet clinical needs. We discovered that splice variant (V1) of HYAL-4 is a first-in-class eukaryotic chondroitinase (Chase), and CD44 is its major substrate. V1 is upregulated in bladder cancer and drives a malignant phenotype. In this study, we investigated whether V1 drives chemotherapy resistance. EXPERIMENTAL DESIGN: V1 expression was measured in muscle-invasive bladder cancer (MIBC) specimens by qRT-PCR and IHC. HYAL-4 wild-type (Wt) and V1 were stably expressed or silenced in normal urothelial and three bladder cancer cell lines. Transfectants were analyzed for chemoresistance and associated mechanism in preclinical models. RESULTS: V1 levels in MIBC specimens of patients who developed metastasis, predicted response to gemcitabine + cisplatin adjuvant/salvage treatment and disease-specific mortality. V1-expressing bladder cells were resistant to gemcitabine but not to cisplatin. V1 expression neither affected gemcitabine influx nor the drug-efflux transporters. Instead, V1 increased gemcitabine metabolism and subsequent efflux of difluorodeoxyuridine, by upregulating cytidine deaminase (CDA) expression through increased CD44-JAK2/STAT3 signaling. CDA inhibitor tetrahydrouridine resensitized V1-expressing cells to gemcitabine. While gemcitabine (25-50 mg/kg) inhibited bladder cancer xenograft growth, V1-expressing tumors were resistant. Low-dose combination of gemcitabine and tetrahydrouridine abrogated the growth of V1 tumors with minimal toxicity. CONCLUSIONS: V1/Chase drives gemcitabine resistance and potentially predicts gemcitabine + cisplatin failure. CDA inhibition resensitizes V1-expressing tumors to gemcitabine. Because several chemotherapy regimens include gemcitabine, our study could have broad significance.