USP22 supports the aggressive behavior of basal-like breast cancer by stimulating cellular respiration.

BACKGROUND: Breast cancer (BC) is the most frequent tumor entity in women worldwide with a high chance of therapeutic response in early- and non-metastatic disease stages. Among all BC subtypes, triple-negative BC (TNBC) is the most challenging cancer subtype lacking effective molecular targets due to the particular enrichment of cancer stem cells (CSCs), frequently leading to a chemoresistant phenotype and metastasis. The Ubiquitin Specific Peptidase 22 (USP22) is a deubiquitinase that has been frequently associated with a CSC-promoting function and intimately implicated in resistance to conventional therapies, tumor relapse, metastasis and overall poor survival in a broad range of cancer entities, including BC. To date, though, the role of USP22 in TNBC has been only superficially addressed. METHODS: The current study utilized the MMTV-cre, Usp22fl/fl transgenic mouse model to study the involvement of USP22 in the stem cell-like properties of the growing mammary tissue. Additionally, we combined high-throughput transcriptomic analyses with publicly available patient transcriptomic data and utilized TNBC culture models to decipher the functional role of USP22 in the CSC characteristics of this disease. RESULTS: Interestingly, we identified that USP22 promotes CSC properties and drug tolerance by supporting the oxidative phosphorylation program, known to be largely responsible for the poor response to conventional therapies in this particularly aggressive BC subtype. CONCLUSIONS: This study suggests a novel tumor-supportive role of USP22 in sustaining cellular respiration to facilitate the drug-tolerant behavior of HER2+-BC and TNBC cells. Therefore, we posit USP22 as a promising therapeutic target to optimize standard therapies and combat the aggressiveness of these malignancies. Video Abstract.

Hemostatic radiotherapy in clinically significant tumor-related bleeding: excellent palliative results in a retrospective analysis of 77 patients.

BACKGROUND: Significant bleeding of tumor sites is a dreaded complication in oncological diseases and often results in clinical emergencies. Besides basic local and interventional procedures, an urgent radiotherapeutic approach can either achieve a bleeding reduction or a bleeding stop in a vast majority of patients. In spite of being used regularly in clinical practice, data reporting results to this therapy approach is still scarce. METHODS: We retrospectively analyzed 77 patients treated for significant tumor-related bleeding at our clinic between 2000 and 2021, evaluating treatment response rate, hemoglobin levels, hemoglobin transfusion necessity, administered radiotherapy dose and overall survival. RESULTS: Response rate in terms of bleeding stop was 88.3% (68/77) in all patients and 95.2% (60/63) in the subgroup, wherein radiotherapy (RT) was completed as intended. Hemoglobin transfusions decreased during treatment in a further subgroup analysis. Median overall survival (OS) was 3.3 months. Patients with primary tumors (PT) of the cervix (carcinoma of the cervix, CC) or endometrium (endometrioid carcinoma, EDC) and patients receiving the full intended RT dose showed statistically significant better OS in a multivariable cox regression model. Median administered dose was 39 Gy, treatment related acute toxicity was considerably low. CONCLUSIONS: Our data show an excellent response rate with a low toxicity profile when administering urgent radiotherapy for tumor related clinically significant bleeding complications. Nonetheless, treatment decisions should be highly individual due to the low median overall survival of this patient group.

Inhibition of Increased Invasiveness of Breast Cancer Cells With Acquired Tamoxifen Resistance by Suppression of CYR61.

BACKGROUND/AIM: Hormone sensitivity-targeted therapy with selective estrogen receptor modulators (SERMs), such as 4-hydroxytamoxifen (4-OHT), is the mainstay of treatment for breast cancers (BCs) that express estrogen receptor α (ERα). However, development of resistance limits this therapy approach. The question arises whether changes associated with 4-OHT resistance could be exploited therapeutically. MATERIALS AND METHODS: First, 4-OHT-resistant sublines of ERα-positive breast carcinoma cell lines MCF-7 and T47D were generated. Viability was assessed by the Alamar Blue assay. Cell invasion was quantified in modified Boyden chambers with Matrigel. Changes in expression of CYR61, S100A4, and ERα were examined by RT-qPCR. Expression of CYR61 was suppressed by transient gene silencing using siRNA. Successful suppression was verified by western blot. Efficacy of 4-OHT treatment was analyzed by quantification of viability using Alamar Blue assay. Correlation of CYR61 levels in patients with luminal A BC to distant metastases-free survival was determined by Kaplan-Meier analysis. RESULTS: ERα-positive MCF-7 and T47D BC cells exhibit an extremely weak invasion rate. Acquired tamoxifen resistance significantly increased the invasive behavior of both tamoxifen-resistant MCF-7-TR and T47D-TR sublines. In addition, expression of CYR61 and S100A4 showed significantly increased levels, whereas expression of ERα was decreased. Suppression of CYR61 expression resulted in a significant decreased invasion rate. In addition, expression of S100A4 was reduced, whereas expression of ERα was increased. Furthermore, suppression of CYR61 resulted in re-sensitization to 4-OHT. High CYR61 levels in patients with luminal A BC resulted in reduced distant metastases-free survival. CONCLUSION: The prometastatic factor CYR61 appears to play an important role in the increased invasiveness of tamoxifen-resistant ERα-positive BC cells. Its suppression leads to a lower invasion rate. Given the few therapeutic options available for tamoxifen-resistant BC, therapy that reduces CYR61 may improve its treatability in future.

Registry Study of the Working Group on Cervical Pathology and Colposcopy (AGCPC) on the Diagnostic Algorithm for the New Cervical Cancer Screening - Initial Data.

Introduction: For the first time since 1971, new regulations were introduced for cervical cancer screening as an organized cancer screening guideline (oKFE-RL) starting 1 January 2020. From the age of 20, a cytological smear test is performed annually, and from the age of 35, so-called co-testing (cytology and test for high-risk HPVs) is performed every three years. In case of abnormalities, the algorithm is used as the basis for investigation. According to this diagnostic algorithm, even so-called low-risk groups receive early colposcopic evaluation. This approach has been heavily debated and serves as the basis for this registry study. Methods: All patients who presented to the centers for a colposcopy as part of the diagnostic algorithm were included after signing an informed consent form. The following findings were obtained: Medical history, colposcopy, histology, and cytology findings, as well as possible therapies and their findings. The aim was to evaluate the frequency of the target lesions cervical intraepithelial neoplasia (CIN) 2+/CIN 3+ in the respective groups. Result: A total of 4763 patients were enrolled in the study from July 2020 to October 2022. As a referral diagnosis, HPV persistence (HPV: human papillomavirus) with group I was determined in 23.9% (1139), HPV persistence with group II-a in 2.1% (100), II-p (ASC-US) in 11.2% (535), and II-g (AGC endocervical NOS) in 1.3% (64). III-p (ASC-H) and III-g (AGC endocervical favor neoplastic) were found in 9.4% (447) and 2.2% (107), respectively, IIID1 (LSIL) in 19% (906), IIID2 (HSIL, moderate dysplasia) in 18.9% (898), IVa-p (HSIL, severe dysplasia) in 10.7% (508), IVa-g (AIS) in 0.7% (31), IVb-p (HSIL with features suspicious for invasion) and IVb-g (AIS with features suspicious for invasion) in 0.3% (15), 0.1% (6), and 7 with suspected invasion V-p (squamous cell carcinoma)/V-g (endocervical adenocarcinoma) (0.1%). In the IVa-p group (HSIL, severe dysplasia), 67.7% had CIN 2+ and 56.5% had CIN 3+, adenocarcinoma in situ (AIS), and adenocarcinoma. If the histology of the excised tissue specifically based on the colposcope findings was also evaluated, CIN 2+ was found in 79.7% of cases, and CIN 3+ in 67.3% of cases. In IIID2 (HSIL, moderate dysplasia), CIN 2+ was detected in 50.9%, and CIN 3+/AIS in 28.3%. After evaluating patients who underwent surgery immediately, this increased to 53.0% for CIN 2+ and 29.3% for CIN 3+/AIS. In IIID1 (LSIL), CIN 2+ was detected in 27.4% and CIN 3+/AIS in 11.7%, and in II-p (ASC-US), CIN 2+ was detected in 23.4% and CIN 3+ and AIS in 10.8%, and in II-g (AGC endocervical NOS), CIN 2+ was detected in 34.4% and CIN 3+ in 23.4%. In the HPV persistence/II-a and I group, 21% showed CIN 2+, and 12.1% showed CIN 3+ and AIS, and 13% showed CIN 2+ and 5.9% showed CIN 3+ and AIS. In patients who were HPV-negative and had further diagnostics performed on the basis of cytologic smear alone, 27.9% had CIN 2+, and 14.1% had CIN 3 and AIS. Discussion: In a synopsis of the present findings of our initial data of the registry study on the new cervical cancer screening, according to the organized early cancer screening guideline (oKFE-RL), we could show that the target lesion CIN 3+ and AIS is detected unexpectedly frequently in a not insignificant proportion, especially in the cytological low-risk group. Currently, we cannot answer whether this can reduce the incidence and mortality of cervical carcinoma, but this could be an initial indication of this and will be reviewed in further long-term evaluations.

RNF40 epigenetically modulates glycolysis to support the aggressiveness of basal-like breast cancer.

Triple-negative breast cancer (TNBC) is the most difficult breast cancer subtype to treat due to the lack of targeted therapies. Cancer stem cells (CSCs) are strongly enriched in TNBC lesions and are responsible for the rapid development of chemotherapy resistance and metastasis. Ubiquitin-based epigenetic circuits are heavily exploited by CSCs to regulate gene transcription and ultimately sustain their aggressive behavior. Therefore, therapeutic targeting of these ubiquitin-driven dependencies may reprogram the transcription of CSC and render them more sensitive to standard therapies. In this work, we identified the Ring Finger Protein 40 (RNF40) monoubiquitinating histone 2B at lysine 120 (H2Bub1) as an indispensable E3 ligase for sustaining the stem-cell-like features of the growing mammary gland. In addition, we found that the RNF40/H2Bub1-axis promotes the CSC properties and drug-tolerant state by supporting the glycolytic program and promoting pro-tumorigenic YAP1-signaling in TNBC. Collectively, this study unveils a novel tumor-supportive role of RNF40 and underpins its high therapeutic value to combat the malignant behavior of TNBC.

Activation of G-Protein-Coupled Estrogen Receptor 1 (GPER1) Reduces Progression of Vulvar Carcinoma Cells.

Whether G protein-coupled estrogen receptor 1 (GPER1) is tumor-promoting or tumor-suppressive depends in part on tumor entity. Little is known about the function of GPER1 in vulvar carcinoma. In this work, we aim to clarify what role GPER1 plays in vulvar cancer, tumor-promoting or tumor-suppressive. Localization of GPER1 in A431 and CAL-39 vulvar carcinoma cells was examined by immunofluorescence. Using a tissue microarray of vulvar neoplasias, the correlation between GPER1 expression and grade of malignancy was investigated. A431 and CAL-39 cells were treated either with GPER1 agonist G1 or antagonist G36. Proliferation was quantified by BrdU assay and viability examined using Resazurin assay. Morphological changes were analyzed by microscopy and measured using ImageJ. Cell migration was analyzed by gap closure assay. Clonogenic potential was tested by colony and sphere formation. Expression of estrogen receptors was examined by Western blot. GPER1 was found consistently expressed in vulvar neoplasia tissues. The immune-reactive score was found to be significantly higher in tissue samples of lymph node metastases and neoplasias with grade 3. In A431 and CAL-39 vulvar carcinoma cells, GPER1 expression was mainly found in the cytoplasm and nuclei. Treatment of A431 and CAL-39 cells with GPER1 agonist G1 resulted in a decrease in proliferation and migration. In addition, colony formation and tumor sphere formation were reduced. Furthermore, morphological signs of necrosis and reduction in cell viability after G1 treatment were observed. The GPER1 antagonist G36 did not have significant effects on vulvar carcinoma cells. Neither agonist G1 nor antagonist G36 treatment resulted in altered expression of estrogen receptors. Activation of GPER1 with GPER1 agonist G1 reduces the tumorigenic potential of the vulvar carcinoma cells. It can be deduced from this that GPER1 appears to have a tumor-suppressive effect in vulvar carcinoma.

Prevalence of Pathogenic Germline Variants in Women with Non-Familial Unilateral Triple-Negative Breast Cancer.

Introduction: International guidelines recommend genetic testing for women with familial breast cancer at an expected prevalence of pathogenic germline variants (PVs) of at least 10%. In a study sample of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC), we have previously shown that women with TNBC diagnosed before the age of 50 years but without a family history of breast or ovarian cancer (sTNBC) meet this criterion. The present study investigates the PV prevalence in BRCA1, BRCA2, and nine additional cancer predisposition genes in an extended sTNBC study sample including a cohort of women with a later age at sTNBC diagnosis. Patients and Methods: In 1,600 women with sTNBC (median age at diagnosis: 41 years, range 19-78 years), we investigated the association between age at diagnosis and PV occurrence in cancer predisposition genes using logistic regression. Results: 260 sTNBC patients (16.2%) were found to have a PV in cancer predisposition genes (BRCA1: n = 170 [10.6%]; BRCA2: n = 46 [2.9%], other: n = 44 [2.8%]). The PV prevalence in women diagnosed between 50 and 59 years (n = 194) was 11.3% (22/194). Logistic regression showed a significant increase in PV prevalence with decreasing age at diagnosis (OR 1.41 per 10 years younger age at diagnosis; 95% confidence interval: 1.21-1.65; p < 0.001). The PV prevalence predicted by the model was above 10% for diagnoses before the age of 56.8 years. Conclusion: Based on the data presented, we recommend genetic testing by gene panel analysis for sTNBC patients diagnosed before the age of 60 years. Due to the still uncertain estimate for women with sTNBC diagnosed above the age of 60 years, further studies are needed.

Optimizing the structure of interdisciplinary tumor boards for effective cancer care.

Introduction: Multi-professional interdisciplinary tumor boards (ITB) are essential institutions to discuss all newly diagnosed, relapsed or complex cancer patients in a team of specialists to find an optimal cancer care plan for each individual patient with regard to national and international clinical practice guidelines, patient´s preference and comorbidities. In a high-volume cancer center, entity-specific ITBs take place at least once a week discussing a large number of patients. To a high level of expertise and dedication, this also requires an enormous amount of time for physicians, cancer specialists and administrative support colleagues, especially for radiologists, pathologists, medical oncologists and radiation oncologists, who must attend all cancer-specific boards according to certification requirements. Methods: In this 15-month prospective German single-center analysis, we examined the established structures of 12 different cancer-specific ITBs at the certified Oncology Center and demonstrate tools helping to optimize processes before, during and after the boards for optimal, time-saving procedures. Results: By changing pathways, introducing revised registration protocols and new digital supports we could show that the workload of preparation by radiologists and pathologists could be reduced significantly by 22.9% (p=<0.0001) and 52.7% (p=<0.0001), respectively. Furthermore, two questions were added to all registration forms about the patient´s need for specialized palliative care support that should lead to more awareness and early integration of specialized help. Discussion: There are several ways to reduce the workload of all ITB team members while maintaining high quality recommendations and adherence to national and international guidelines.

MSX1-expression during the different phases in healthy human endometrium.

PURPOSE: The human endometrium consists of different layers (basalis and functionalis) and undergoes different phases throughout the menstrual cycle. In a former paper, our research group was able to describe MSX1 as a positive prognosticator in endometrial carcinomas. The aim of this study was to examine the MSX1 expression in healthy endometrial tissue throughout the different phases to gain more insight on the mechanics of MSX-regulation in the female reproductive system. MATERIALS AND METHODS: In this retrospective study, we investigated a total of 17 normal endometrial tissues (six during proliferative phase and five during early and six during late secretory phase). We used immunohistochemical staining and an immunoreactive score (IRS) to evaluate MSX1 expression. We also investigated correlations with other proteins, that have already been examined in our research group using the same patient collective. RESULTS: MSX1 is expressed in glandular cells during the proliferative phase and downregulated at early and late secretory phase (p = 0.011). Also, a positive correlation between MSX1 and the progesterone-receptor A (PR-A) (correlation coefficient (cc) = 0.0671; p = 0.024), and the progesterone receptor B (PR-B) (cc = 0.0691; p = 0.018) was found. A trend towards negative correlation was recognized between MSX1 and Inhibin Beta-C-expression in glandular cells (cc = - 0.583; p-value = 0.060). CONCLUSION: MSX1 is known as a member of the muscle segment homeobox gene family. MSX1 is a p53-interacting protein and overexpression of homeobox MSX1 induced apoptosis of cancer cells. Here we show that MSX1 is expressed especially in the proliferative phase of glandular epithelial tissue of the normal endometrium. The found positive correlation between MSX1 and progesterone receptors A and B confirms the results of a previous study on cancer tissue by our research group. Because MSX1 is known to be downregulated by progesterone, the found correlation of MSX1 and both PR-A and -B may represent a direct regulation of the MSX1 gene by a PR-response element. Here further investigation would be of interest.

Knockdown of G Protein-coupled Estrogen Receptor 1 (GPER1) Enhances Tumor-supportive Properties in Cervical Carcinoma Cells.

BACKGROUND/AIM: A wide variety of answers can be found regarding the question of whether G-protein-coupled estrogen receptor 1 (GPER1) is tumor supportive or tumor suppressive. In cervical carcinoma (CC), the function of GPER1 is poorly understood. In this work, we aimed to clarify what role GPER1 plays in CC, tumor promoting of tumor suppressive. MATERIALS AND METHODS: Transient GPER1 silencing was conducted using RNAi and approved by RT-qPCR. Clonogenic potential was tested by colony and sphere formation. Expression of SERPINE1/PAI-1 was quantified by RT-qPCR and Western blot. Morphological changes were analyzed using Phalloidin staining. Localization of GPER1 in tumor spheres was examined by immunofluorescence. RESULTS: After GPER1 knockdown, more colonies formed in HeLa and SiHa, and larger colonies formed in C33-A and SiHa CC cells. Size of HeLa and SiHa tumor spheres was also increased. In addition, number of HeLa tumor spheres was elevated, and larger secondary colonies were present. C33-A only formed tumor sphere-like clusters showing no differences in number and size. Phalloidin staining revealed greater cellular length-to-width ratio and increased average filopodia length. Expression of SERPINE1/PAI-1 was increased in HeLa and decreased in C33-A. In SiHa cells, SERPINE1 was slightly decreased, whereas the protein PAI-1 was increased. Strong expression of GPER1 was detectable in peripheral areas and in sprouts of tumor spheres. CONCLUSION: GPER1 appears to be tumor suppressive in CC, as GPER1 knockdown provoked increased stem cell properties and increased migration/invasion. EMT also appears to be enhanced. Of interest is the increase in SERPINE1/PAI-1 expression after GPER1 knockdown.

Suppression of G Protein-coupled Estrogen Receptor 1 (GPER1) Enhances the Anti-invasive Efficacy of Selective ERß Agonists.

BACKGROUND/AIM: G protein-coupled estrogen receptor 1 (GPER1) is often over-expressed in triple negative breast cancer (TNBC). GPER1 is responsible for many of the non-genomic, membrane-initiated effects of estrogens. Therefore, we have analyzed the effects of GPER1 knockdown using specific siRNA. MATERIALS AND METHODS: Transient GPER1 silencing was conducted using RNA interference and confirmed by RT-PCR and western blot. Viability of human breast cancer cell lines MDA-MB 231 and HCC 1806 was tested using AlamarBlue assay. Cell invasion was analyzed by assessment of cell migration rate through an artificial basement membrane in a modified Boyden chamber. RESULTS: Viability of both cell lines was slightly decreased after suppression of GPER1 expression. Knockdown of GPER1 resulted in a significantly reduced invasion of the TNBC cells. The anti-invasive effect of selective ERß agonists was significantly stronger after knockdown of GPER1 expression. In addition, the efficacy of tamoxifen treatment was significantly increased after suppression of GPER1 expression. CONCLUSION: Suppression of GPER1 reduced the metastatic behavior of TNBC cells, improved the anti-invasive efficacy of selective ERß agonists and sensitized cells to 4OH-tamoxifen.

ROBO3s: a novel ROBO3 short isoform promoting breast cancer aggressiveness.

Basal-like breast cancer (BLBC) is a highly aggressive breast cancer subtype frequently associated with poor prognosis. Due to the scarcity of targeted treatment options, conventional cytotoxic chemotherapies frequently remain the standard of care. Unfortunately, their efficacy is limited as BLBC malignancies rapidly develop resistant phenotypes. Using transcriptomic and proteomic approaches in human and murine BLBC cells, we aimed to elucidate the molecular mechanisms underlying the acquisition of aggressive and chemotherapy-resistant phenotypes in these mammary tumors. Specifically, we identified and characterized a novel short isoform of Roundabout Guidance Receptor 3 (ROBO3s), upregulated in BLBC in response to chemotherapy and encoding for a protein variant lacking the transmembrane domain. We established an important role for the ROBO3s isoform, mediating cancer stem cell properties by stimulating the Hippo-YAP signaling pathway, and thus driving resistance of BLBC cells to cytotoxic drugs. By uncovering the conservation of ROBO3s expression across multiple cancer types, as well as its association with reduced BLBC-patient survival, we emphasize its potential as a prognostic marker and identify a novel attractive target for anti-cancer drug development.

Like Brothers in Arms: How Hormonal Stimuli and Changes in the Metabolism Signaling Cooperate, Leading HPV Infection to Drive the Onset of Cervical Cancer.

Despite all precautionary actions and the possibility of using vaccinations to counteract infections caused by human papillomaviruses (HPVs), HPV-related cancers still account for approximately 5% of all carcinomas. Worldwide, many women are still excluded from adequate health care due to their social position and origin. Therefore, immense efforts in research and therapy are still required to counteract the challenges that this disease entails. The special thing about an HPV infection is that it is not only able to trick the immune system in a sophisticated way, but also, through genetic integration into the host genome, to use all the resources available to the host cells to complete the replication cycle of the virus without activating the alarm mechanisms of immune recognition and elimination. The mechanisms utilized by the virus are the metabolic, immune, and hormonal signaling pathways that it manipulates. Since the virus is dependent on replication enzymes of the host cells, it also intervenes in the cell cycle of the differentiating keratinocytes and shifts their terminal differentiation to the uppermost layers of the squamocolumnar transformation zone (TZ) of the cervix. The individual signaling pathways are closely related and equally important not only for the successful replication of the virus but also for the onset of cervical cancer. We will therefore analyze the effects of HPV infection on metabolic signaling, as well as changes in hormonal and immune signaling in the tumor and its microenvironment to understand how each level of signaling interacts to promote tumorigenesis of cervical cancer.

HDAC8 suppresses the epithelial phenotype and promotes EMT in chemotherapy-treated basal-like breast cancer.

BACKGROUND: Basal-like breast cancer (BLBC) is one of the most aggressive malignant diseases in women with an increased metastatic behavior and poor prognosis compared to other molecular subtypes of breast cancer. Resistance to chemotherapy is the main cause of treatment failure in BLBC. Therefore, novel therapeutic strategies counteracting the gain of aggressiveness underlying therapy resistance are urgently needed. The epithelial-to-mesenchymal transition (EMT) has been established as one central process stimulating cancer cell migratory capacity but also acquisition of chemotherapy-resistant properties. In this study, we aimed to uncover epigenetic factors involved in the EMT-transcriptional program occurring in BLBC cells surviving conventional chemotherapy. RESULTS: Using whole transcriptome data from a murine mammary carcinoma cell line (pG-2), we identified upregulation of Hdac4, 7 and 8 in tumor cells surviving conventional chemotherapy. Subsequent analyses of human BLBC patient datasets and cell lines established HDAC8 as the most promising factor sustaining tumor cell viability. ChIP-sequencing data analysis identified a pronounced loss of H3K27ac at regulatory regions of master transcription factors (TFs) of epithelial phenotype like Gata3, Elf5, Rora and Grhl2 upon chemotherapy. Interestingly, impairment of HDAC8 activity reverted epithelial-TFs levels. Furthermore, loss of HDAC8 activity sensitized tumor cells to chemotherapeutic treatments, even at low doses. CONCLUSION: The current study reveals a previously unknown transcriptional repressive function of HDAC8 exerted on a panel of transcription factors involved in the maintenance of epithelial cell phenotype, thereby supporting BLBC cell survival to conventional chemotherapy. Our data establish HDAC8 as an attractive therapeutically targetable epigenetic factor to increase the efficiency of chemotherapeutics.

Case Report: Collapsing Focal Segmental Glomerulosclerosis After Initiation of Ado-Trastuzumab Emtansine Therapy.

Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate consisting of the monoclonal antibody trastuzumab linked to the maytansinoid DM1 with potential antineoplastic activity and is approved for human epidermal growth factor receptor 2 (HER2)-positive breast cancer. An analysis of the US Food and Drug Administration (FDA) Adverse Event Reporting System identified 124/1,243 (10%) renal adverse events for trastuzumab. However, there are no published case reports describing kidney biopsy findings related to nephrotoxicity of either trastuzumab or T-DM1. We report kidney biopsy findings in a case of nephrotic range proteinuria due to collapsing focal segmental glomerulosclerosis (FSGS) and tubular injury after initiation of T-DM1 therapy. After systematic exclusion of other causes, it is likely that the observed collapsing FSGS was associated with the prior initiation of T-DM1 therapy. This is further supported by the clinical course with improvement of proteinuria and kidney function 3 weeks after discontinuation of T-DM1 therapy without further specific treatment. In summary, we provide the first report of kidney biopsy findings in a case of nephrotic range proteinuria after initiation of T-DM1 therapy due to collapsing FSGS. This issue is especially relevant since T-DM1 is widely used, and nephrologists have to be aware of this potentially rare but severe complication.

Inhibition of Metabolism as a Therapeutic Option for Tamoxifen-Resistant Breast Cancer Cells.

Cancer cells have an increased need for glucose and, despite aerobic conditions, obtain their energy through aerobic oxidation and lactate fermentation, instead of aerobic oxidation alone. Glutamine is an essential amino acid in the human body. Glutaminolysis and glycolysis are crucial for cancer cell survival. In the therapy of estrogen receptor α (ERα)-positive breast cancer (BC), the focus lies on hormone sensitivity targeting therapy with selective estrogen receptor modulators (SERMs) such as 4-hydroxytamoxifen (4-OHT), although this therapy is partially limited by the development of resistance. Therefore, further targets for therapy improvement of ERα-positive BC with secondary 4-OHT resistance are needed. Hence, increased glucose requirement and upregulated glutaminolysis in BC cells could be used. We have established sublines of ERα-positive MCF7 and T47D BC cells, which were developed to be resistant to 4-OHT. Further, glycolysis inhibitor 2-Deoxy-D-Glucose (2-DG) and glutaminase inhibitor CB-839 were analyzed. Co-treatments using 4-OHT and CB-839, 2-DG and CB-839, or 4-OHT, 2-DG and CB-839, respectively, showed significantly stronger inhibitory effects on viability compared to single treatments. It could be shown that tamoxifen-resistant BC cell lines, compared to the non-resistant cell lines, exhibited a stronger reducing effect on cell viability under co-treatments. In addition, the tamoxifen-resistant BC cell lines showed increased expression of proto-oncogene c-Myc compared to the parental cell lines. This could be reduced depending on the treatment. Suppression of c-Myc expression using specific siRNA completely abolished resistance to 4OH-tamoxifen. In summary, our data suggest that combined treatments affecting the metabolism of BC are suitable depending on the cellularity and resistance status. In addition, the anti-metabolic treatments affected the expression of the proto-oncogene c-Myc, a key player in the regulation of cancer cell metabolism.

HPV and Other Microbiota; Who's Good and Who's Bad: Effects of the Microbial Environment on the Development of Cervical Cancer-A Non-Systematic Review.

Cervical cancer is responsible for around 5% of all human cancers worldwide. It develops almost exclusively from an unsolved, persistent infection of the squamocolumnar transformation zone between the endo- and ecto-cervix with various high-risk (HR) human papillomaviruses (HPVs). The decisive turning point on the way to persistent HPV infection and malignant transformation is an immune system weakened by pathobionts and oxidative stress and an injury to the cervical mucosa, often caused by sexual activities. Through these injury and healing processes, HPV viruses, hijacking activated keratinocytes, move into the basal layers of the cervical epithelium and then continue their development towards the distal prickle cell layer (Stratum spinosum). The microbial microenvironment of the cervical tissue determines the tissue homeostasis and the integrity of the protective mucous layer through the maintenance of a healthy immune and metabolic signalling. Pathological microorganisms and the resulting dysbiosis disturb this signalling. Thus, pathological inflammatory reactions occur, which manifest the HPV infection. About 90% of all women contract an HPV infection in the course of their lives. In about 10% of cases, the virus persists and cervical intra-epithelial neoplasia (CIN) develops. Approximately 1% of women with a high-risk HPV infection incur a cervical carcinoma after 10 to 20 years. In this non-systematic review article, we summarise how the sexually and microbial mediated pathogenesis of the cervix proceeds through aberrant immune and metabolism signalling via CIN to cervical carcinoma. We show how both the virus and the cancer benefit from the same changes in the immune and metabolic environment.

German evidence and consensus-based (S3) guideline: Vaccination recommendations for the prevention of HPV-associated lesions.

Anogenital and oropharyngeal infections with human papilloma viruses (HPV) are common. Clinically manifest disease may significantly impact quality of life; the treatment of HPV-associated lesions is associated with a high rate of recurrence and invasive neoplasms, such as cervical, anal, vulvar, penile, and oropharyngeal cancers, which are characterized by significant morbidity and mortality. Vaccination against HPV is an effective and safe measure for the primary prevention of HPV-associated lesions, but immunization rates are still low in Germany. The present publication is an abridged version of the German evidence and consensus-based guideline "Vaccination recommendations for the prevention of HPV-associated lesions", which is available on the website of the German Association of the Scientific Medical Societies (AWMF). On the basis of a systematic review with meta-analyses, a representative panel developed and agreed upon recommendations for the vaccination of different populations against HPV. In addition, consensus-based recommendations were developed for specific issues relevant to everyday practice. Based on current evidence and a representative expert consensus, these recommendations are intended to provide guidance in a field in which there is often uncertainty and in which both patients and health care providers are sometimes confronted with controversial and emotionally charged points of view.