Diagnostic and Therapeutic Challenges of Oligosymptomatic Vesicovaginal Fistula in the Complex Case of Endometriosis.

Endometriosis is a complex condition causing surgical challenges, sometimes leading to urogynecological complications, the diagnosis and treatment of which are not always obvious. We present a case of a 46-year-old woman with a history of severe endometriosis and adenomyosis who developed an oligosymptomatic vesicovaginal fistula (VVF) as a complication of surgery. The patient's medical history included multiple surgeries for endometriosis, a cesarean section, and a laparoscopic hysterectomy. After the excision of the full-thickness infiltration of the urinary bladder, she experienced postoperative bowel obstruction treated by laparotomy. Subsequent urinary complications of bladder healing were eventually recognized as oligosymptomatic VVF. Symptoms of VVFs may vary, making a diagnosis challenging, especially when the lesion is narrow. Imaging techniques such as cystoscopy and cystography are helpful for diagnosis. The treatment options for VVFs range from surgical repair to conservative methods, like bladder catheterization, hormonal therapy, and platelet-rich plasma (PRP) injections, depending on the lesions' size and location. In this case, the patient's VVF was treated with PRP injections, a low-invasive method in urogynecology. PRP, known for its pleiotropic role, is increasingly used in medicine, including gynecology. The patient's fistula closed after 6 weeks from the PRP session, highlighting the potential of this conservative treatment modality.

Immunological and Metabolic Causes of Infertility in Polycystic Ovary Syndrome.

Infertility has been recognized as a civilizational disease. One of the most common causes of infertility is polycystic ovary syndrome (PCOS). Closely interrelated immunometabolic mechanisms underlie the development of this complex syndrome and lead to infertility. The direct cause of infertility in PCOS is ovulation and implantation disorders caused by low-grade inflammation of ovarian tissue and endometrium which, in turn, result from immune and metabolic system disorders. The systemic immune response, in particular the inflammatory response, in conjunction with metabolic disorders, insulin resistance (IR), hyperadrenalism, insufficient secretion of progesterone, and oxidative stress lead not only to cardiovascular diseases, cancer, autoimmunity, and lipid metabolism disorders but also to infertility. Depending on the genetic and environmental conditions as well as certain cultural factors, some diseases may occur immediately, while others may become apparent years after an infertility diagnosis. Each of them alone can be a significant factor contributing to the development of PCOS and infertility. Further research will allow clinical management protocols to be established for PCOS patients experiencing infertility so that a targeted therapy approach can be applied to the factor underlying and driving the "vicious circle" alongside symptomatic treatment and ovulation stimulation. Hence, therapy of fertility for PCOS should be conducted by interdisciplinary teams of specialists as an in-depth understanding of the molecular relationships and clinical implications between the immunological and metabolic factors that trigger reproductive system disorders is necessary to restore the physiology and homeostasis of the body and, thus, fertility, among PCOS patients.

Progesterone and Its Metabolites Play a Beneficial Role in Affect Regulation in the Female Brain.

Premenstrual dysphoric disorder is a female affective disorder that is defined by mood symptoms. The condition is linked to unstable progesterone concentrations. Progestin supplementation is given in cases of threatened or recurrent miscarriage and for luteal phase support. Progesterone is essential for implantation, immune tolerance, and modulation of uterine contractility. For a long time, the administration of progestins was associated with an unfavorable impact on mood, leading to negative affect, and, therefore, was contraindicated in existing mood disorders. Establishing the role of the natural progesterone derivative allopregnanolone in advances in the treatment of postpartum depression has shed new light on the general pathophysiology of mood disorders. Allopregnanolone directly interacts with gamma-aminobutyric acid type A (GABA-A) receptors even at nanomolar concentrations and induces significant anti-depressant, anti-stress, sedative, and anxiolytic effects. Postpartum depression is caused by a rapid drop in hormones and can be instantly reversed by the administration of allopregnanolone. Premenstrual dysphoric disorder can also be considered to result from insufficient neuroactive steroid action due to low progesterone derivative concentration, unstable hormone levels, or decreased receptor sensitivity. The decrease in progesterone levels in perimenopause is also associated with affective symptoms and an exacerbation of some psychosomatic syndromes. Bioidentical progesterone supplementation encounters several obstacles, including limited absorption, first-pass effect, and rapid metabolism. Hence, non-bioidentical progestins with better bioavailability were widely applied. The paradoxical, unfavorable effect of progestins on mood can be explained by the fact that progestins suppress ovulation and disturb the endocrine function of the ovary in the luteal phase. Moreover, their distinct chemical structure prevents their metabolism to neuroactive, mood-improving derivatives. A new understanding of progesterone-related mood disorders can translate the study results from case series and observational studies to cohort studies, clinical trials, and novel, effective treatment protocols being developed.

Successful Implementation of Menstrual Cycle Biomarkers in the Treatment of Infertility in Polycystic Ovary Syndrome-Case Report.

Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility. Absent, impaired, or rare ovulation induces progesterone deficiency in the luteal phase, which is a critical problem in PCOS. A usual pattern of progesterone administration from a fixed and arbitrary pre-determined day of a menstrual cycle may preserve infertility but can easily be avoided. We present the case of a 29-year-old infertile woman who had been ineffectively treated for over two years. We introduced a line of therapy that was suited to her individual menstrual cycle by implementing biomarker recording. Supplementation based on a standardized observation of the basal body temperature (BBT) and cervical mucus stopped the vicious circle of absent ovulation and hyperandrogenism, restoring regular bleeding, ovulation cycles, and fertility. The implementation of a reliable fertility awareness method (FAM), accompanied by a standardized teaching methodology and periodic review of the observations recorded by the patient, validated through an ultrasound examination and plasma gonadotropins, estrogens, and progesterone concentrations, is key to achieving therapeutic success. The presented case is an example of a clinical vignette for many patients who have successfully managed to improve their fertility and pregnancy outcomes by applying the principles of a personalized treatment approach together with gestagens by recording their fertility biomarkers.

Inhibin-B and FSH Are Good Indicators of Spermatogenesis but Not the Best Indicators of Fertility.

Biochemical markers of spermatogenesis and fertility assessment are important in the practical management of infertile males and the determination of an individual's prognosis. We performed an analysis on 100 males with a male infertility factor. The following study inclusion parameters were analyzed: seminogram, FSH, LH, testosterone, estradiol, prolactin, TSH, and inhibin B concentrations. The patients were subsequently treated by reproductive endocrinologists in accordance with AUA/ASRM and EAU guidelines. The reproductive status was evaluated over a period of 3 years. We found a strong correlation of sperm count with inhibin B (r = 0.74, p < 0.001) and FSH concentration levels (r = −0.46, p < 0.001). Among 95 patients at follow-up, pregnancies occurred for 59 of their partners (48 spontaneous, 5 after IVF−ET, and 6 after IUI). Thirty-six patients remained childless despite the therapy. Sperm count and inhibin B level were the best predictors of natural fertilization (ROC AUC: 0.86 and 0.84; cut-off: 2.7 mln/mL and 45 pg/mL). Although inhibin B and FSH can be used to evaluate spermatogenesis and fertility, the initial sperm concentration appeared to be the best predictor of success. Pregnancy was achieved in a surprisingly large proportion of patients with a very low concentration of inhibin B and a low initial sperm count. It is noteworthy that 81% of the pregnancies were achieved without medically assisted reproduction.

The Urogynecology Section of the Polish Society of Gynecologists and Obstetricians Guidelines for the diagnostic assessment of pelvic organ prolapse.

OBJECTIVES: The aim of the team appointed by the Board of the Urogynecology Section of the Polish Society of Gynecologists and Obstetricians (PSGO) was to develop this interdisciplinary Guideline for the diagnostic assessment of pelvic organ prolapse (POP) in women, based on the available literature, expert knowledge and opinion, as well as everyday practice. MATERIAL AND METHODS: A review of the literature, including current international guidelines and earlier PSGO recommendations (2010-2020) about POP, was conducted. RESULTS: The steps of the diagnostic assessment for patients with POP, subdivided into initial and specialized diagnostics, have been presented. Indications for specialized diagnostic assessment have also been listed. In case of surgical treatment, the patient may be referred solely based on the initial diagnostics or after certain elements of the specialized diagnostics have been completed. CONCLUSIONS: Due to inconclusive data, the scope of the diagnostic process for POP is individualized for each patient and depends on patient-reported symptoms, initial diagnostic findings, surgical history, management plan, availability of the equipment, and cost.

Immunology and Immunotherapy of Endometriosis.

Endometriosis is one of the most common gynecological and systemic diseases, with a remarkable immune background. Patients suffer from pain and fertility reduction. Due to the distinct immune component, an immunotherapeutic approach may gain importance in the future. In endometriosis, shifts in the cell fractions of the immune system are well known. Moreover, hypoxia concomitant with inflammation causes a disturbed immune response. The removal of endometriosis has a therapeutic effect, normalizes the immune disorders, and remains the most effective causative treatment in terms of pain and infertility. A key issue is whether a similar effect can be achieved for fertility with non-invasive immunotherapy where surgery is inadvisable or cannot be performed for various reasons. Numerous immunotherapy trials, including vaccines, were conducted on animals only, although the research is encouraging. Among the promising methods of non-specific immunotherapy is the administration of an ethiodized oil contrast. Moreover, due to the significant successes of immunotherapy in oncology, the possibility of immunotherapy affecting NK cells has been postulated. NK cells are responsible for the surveillance and apoptosis of ectopic cells. Expanding the arsenal of endometriosis treatment by immunotherapy is promising due to the significant contribution of immunological factors and the limitations of current treatment methods.

Epithelial Cells of Deep Infiltrating Endometriosis Harbor Mutations in Cancer Driver Genes.

Endometriosis is an inflammatory condition manifested by the presence of endometrial-like tissue outside of the uterine cavity. The most common clinical presentations of endometriosis are dysmenorrhea, infertility, and severe pelvic pain. Few hypotheses attempt to explain the pathogenesis of endometriosis; however, none of the theories have been fully confirmed or considered universal. We examined somatic mutations in eutopic endometrium samples, deep endometriotic nodules and peripheral blood from 13 women with deep endometriosis of the rectovaginal space. Somatic variants were identified in laser microdissected samples using next-generation sequencing. A custom panel of 1296 cancer-related genes was employed, and selected genes representing cancer drivers and non-drivers for endometrial and ovarian cancer were thoroughly investigated. All 59 detected somatic variants were of low mutated allele frequency (<10%). In deep ectopic lesions, detected variants were significantly more often located in cancer driver genes, whereas in eutopic endometrium, there was no such distribution. Our results converge with other reports, where cancer-related mutations were found in endometriosis without cancer, particularly recurrent KRAS mutations. Genetic alterations located in ectopic endometriotic nodules could contribute to their formation; nevertheless, to better understand the pathogenesis of this disease, more research in this area must be performed.

Supplementation of dehydroepiandrosterone (DHEA) in pre- and postmenopausal women - position statement of expert panel of Polish Menopause and Andropause Society.

Dehydroepiandrosterone (DHEA) concentration decreases with age, therefore, DHEA has been considered a hormone that reduces the symptoms associated with aging, so the usefulness of DHEA in premenopausal and postmenopausal women, and the options of hormone therapy have received a large amount of attention. The effectiveness of DHEA in the premenopausal women remains unclear, while in postmenopausal women with coexisting estrogens deficiency is controversial. Despite many years of study, the use of DHEA is still controversial, especially regarding its effectiveness. The aim of present article was to evaluate DHEA specific effects on metabolic parameters, bone mineral density, insulin resistance as well as the therapeutic potential of DHEA in pre- and postmenopausal women using measures of sexual activity, cognition and well-being. The summary of this article is the position statement of expert group of the Polish Menopause and Andropause Society regarding the efficacy and safety of DHEA supplementation in women. We concluded, that currently available clinical trials and meta-analyses indicate that DHEA supplementation is effective in women with adrenal insufficiency and chronically treated with exogenous glucocorticoids, postmenopausal women with low bone mineral density and/or osteoporosis, premenopausal women with sexual disorders and low libido, and in women with vulvovaginal atrophy due to menopause or genitourinary syndrome of menopause. Currently available clinical trials also suggest that DHEA supplementation is probably effective in postmenopausal women with hypoactive sexual disorders, infertile women with diminished ovarian reserve, women suffering from depression and anxiety, and women with obesity and insulin resistance. No serious adverse effects have been reported.

Facile Fabrication of Surface-Imprinted Macroporous Films for Chemosensing of Human Chorionic Gonadotropin Hormone.

We present an improved approach for the preparation of highly selective and homogeneous molecular cavities in molecularly imprinted polymers (MIPs) via the combination of surface imprinting and semi-covalent imprinting. Toward that, first, a colloidal crystal mold was prepared via the Langmuir-Blodgett (LB) technique. Then, human chorionic gonadotropin (hCG) template protein was immobilized on the colloidal crystal mold. Later, hCG derivatization with electroactive functional monomers via amide chemistry was performed. In a final step, optimized potentiostatic polymerization of 2,3'-bithiophene enabled depositing an MIP film as the macroporous structure. This synergistic strategy resulted in the formation of molecularly imprinted cavities exclusively on the internal surface of the macropores, which were accessible after dissolution of silica molds. The recognition of hCG by the macroporous MIP film was transduced with the help of electric transducers, namely, extended-gate field-effect transistors (EG-FET) and capacitive impedimetry (CI). These readout strategies offered the ability to create chemosensors for the label-free determination of the hCG hormone. Other than the simple confirmation of pregnancy, hCG assay is a common tool for the diagnosis and follow-up of ectopic pregnancy or trophoblast tumors. Concentration measurements with these EG-FET and CI-based devices allowed real-time measurements of hCG in the range of 0.8-50  and 0.17-2.0 fM, respectively, in 10 mM carbonate buffer (pH = 10). Moreover, the selectivity of chemosensors with respect to protein interferences was very high.

Post-finasteride syndrome - does it really exist?

Inhibitors of 5α-steroid reductase are drugs used to treat androgen-dependent conditions including prostate diseases and androgenic alopecia. Finasteride was the first on the market and is currently the most widely used inhibitor. Dutasteride was the second inhibitor to be approved and has a similar safety profile. Common adverse events of treatment consist of sexual disorders and a negative affect balance. It was described that the prolonged use of 5α-steroid reductase inhibitors in patients with alopecia can cause persistent side effects called a post-finasteride syndrome (PFS), that is not just a simple coexistence of events, but rather a definite syndrome with an iatrogenic background. PFS occurs in susceptible individuals even after small doses of the drug and can last for a long time after the discontinuation of treatment. A deterioration in the quality of life in affected individuals does not justify use of the drug. Wider recognition of PFS symptoms, its incidence, course, prevention, and treatment possibilities will allow the indications for drug use to be reconsidered and treatment to be more personalized. Knowledge about PFS will also help to provide the best treatment for affected individuals and to properly educate patients before obtaining an informed consent for therapy with 5α-steroid reductase inhibitors.

The bimodal role of matrix metalloproteinases and their inhibitors in etiology and pathogenesis of endometriosis (Review).

Aberrant regulation of matrix metalloproteinases (MMPs) may be the primary cause of endometrial lesion formation in a group of predisposed women. Prospect for the genuine origin of endometriosis is ongoing, since retrograde menstruation leads to presence of endometrial debris in peritoneal cavity of many women, which do not experience endometriosis. Tissue remodeling is regulated precisely by a balance of MMPs and their inhibitors. Interplay between factors enhancing and suppressing matrix turnover is crucial for cyclic preparation of endometrium for embryo implantation, and endometrial shedding and renewal in physiology of primates. Disorders of the regulation of matrix remodeling leads to augmentation of implantation and invasive growth of ectopic endometrial tissue. Moreover, endometriosis­induced changes in the matrix balance leads to adhesion formation, ovulatory dysfunction and fertility impairment. The review summarizes the current knowledge regarding the regulation of extracellular matrix turnover in the physiology of the endometrial cycle and in the development of endometriosis, as well as the pathophysiology of ovulatory dysfunction in endometriotic women. Therapeutic modalities utilizing modulation of tissue remodeling were discussed.

The Relationship Between Health-Related Quality of Life and Anabolic Hormone Levels in Middle-Aged and Elderly Men With Prediabetes: A Cross-Sectional Study.

The aim of this study was to compare health-related quality of life (HRQoL) between men with prediabetes (PD) and a control group as well as to investigate the relationship between HRQoL and anabolic hormones. The analysis was carried out in 176 middle-aged (40-59 years) and elderly (60 80 years) men with PD, and 184 control peers. PD was defined according the American Diabetes Association and HRQoL was assessed by the SF-36 questionnaire. Total testosterone (TT), calculated free testosterone, dehydroepiandrosterone sulfate (DHEAS), and insulin-like growth factor 1 (IGF-1) were measured. Analysis of the standardized physical and mental component summary scores (SF-36p and SF-36m) revealed that patients with PD had lower SF-36p and SF-36m than control group ( p < .02 and p < .001). Middle-aged men with PD had lower SF-36p and SF-36m than control peers, whereas elderly men with PD had lower only SF-36p. In men with PD negative correlations between glycated hemoglobin (HbA1c) and SF-35m score ( r = -0.3768; p = .02) and between HbA1c and SF-36p score ( r = -0.3453; p = .01) were reported. In middle-aged prediabetic men, SF-36p was associated with high free testosterone and low HbA1c while SF-36m with high TT and high DHEAS. In elderly patients with PD, SF-36p was associated with high TT, high IGF-1, and low HbA1c, while SF-36m correlated with high free testosterone and high DHEAS. In conclusion, PD in men is associated with decreased HRQoL in comparison with healthy men, and generally better quality of life is associated with higher testosterone, higher free testosterone, higher DHEAS, and lower HbA1c.

Late-onset lattice corneal dystrophy without typical lattice lines caused by a novel mutation in the TGFBI gene.

PURPOSE: The aim of this study was to report the clinical, histopathological, and molecular findings in a patient with late-onset lattice corneal dystrophy (LCD) without typical lattice lines and a novel mutation in the TGFBI gene. METHODS: Corneal lesions were visualized by slit-lamp examination and by in vivo confocal microscopy. Histopathological examination was performed on the patient's corneal specimen obtained during a deep anterior lamellar keratoplasty. By using genomic DNA as a template, all coding regions of the TGFBI gene were amplified and directly sequenced. The presence of the mutation was verified using restriction endonuclease digestion. Eight different computational methods and multiple sequence alignments were used to predict the pathogenicity of the novel genetic variant. RESULTS: The corneal phenotype was characterized by the presence within the stroma of round, oval, and short comma-shaped structures with indistinct margins. Lattice lines were not visible. Histopathological study revealed positive Congo red areas of amyloid deposits typical for LCD. A novel heterozygous missense mutation p.Leu565Pro was identified in exon 13 of the TGFBI gene. The amino acid substitution was unambiguously predicted to have a high pathogenic potential. CONCLUSIONS: The mutant codon 565 is located at the C-terminus in the region corresponding to a highly conserved amino acid in the fourth fascilin domain of the TGFBI protein. The novel variant expands the spectrum of TGFBI mutations causing LCD and located in this region. An increased number of known mutations will facilitate future studies of genotype-phenotype correlations and molecular pathogenesis of corneal dystrophies.

CD4⁺ CD25⁺ FOXP3⁺ regulatory T cells in peripheral blood and peritoneal fluid of patients with endometriosis.

STUDY QUESTION: Is endometriosis associated with changes in CD4⁺ CD25⁺ FOXP3⁺ regulatory T cells (Treg cells)? SUMMARY ANSWER: Endometriosis is associated with disturbed compartmentalization of CD25(high) FOXP3⁺ Treg cells. WHAT IS KNOWN ALREADY: Endometriosis is associated with an abrogated immune response and displays some features of an autoimmune disorder. Treg cells play a part in the development of autoimmune reactions; however, their role in pathogenesis of endometriosis is still poorly recognized. STUDY DESIGN, SIZE AND DURATION: Case-control study comparing 17 women with laparoscopically and histopathologically confirmed ovarian endometriosis with 15 control women without visible endometriosis foci, pelvic inflammation or related pathology who were subjected to laparoscopic surgery between 2010 and 2011. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Peripheral blood and peritoneal fluid were collected during laparoscopy and T cell subpopulations were analysed by flow cytometry using specific monoclonal antibodies recognizing CD4⁺, CD25⁺ and FOXP3⁺ markers. MAIN RESULTS: The percentage of CD25(high) FOXP3⁺ Treg cells was significantly decreased in the peripheral blood of women with ovarian endometriosis compared with control women. On the other hand, the proportion of these cells was significantly increased in the peritoneal fluid of women with endometriosis. LIMITATIONS, REASONS FOR CAUTION: The present study is limited to patients with ovarian endometrioma and further investigations are needed, including patients with lower grade of endometriosis. WIDER IMPLICATIONS OF THE FINDINGS: The present results suggest that Treg cells may play a part in immunopathogenesis of endometriosis being responsible for abrogated local cellular immune responses and facilitation and development of autoimmune reactions. Treg cells may be thus a potential target in the treatment of endometriosis. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by 1M15/N/2011 and NK1W grants from the I Faculty of Medicine, Warsaw Medical University. None of the authors has any competing interests to declare.

Regulation of expression of stromal-derived factor-1 receptors: CXCR4 and CXCR7 in human rhabdomyosarcomas.

Rhabdomyosarcomas (RMS) express CXCR4 and CXCR7 receptors that bind prometastatic alpha-chemokine stromal-derived factor-1 (SDF-1). In this report, we analyzed the activity of both promoters in a model of less metastatic human embryonal-RMS cell line (RD) and more metastatic alveolar-like RMS (RD cells transduced with paired box gene 3/forkhead homologue; PAX3-FKHR fusion gene). First, CXCR4 is barely detectable in RD and becomes upregulated in RD/PAX3-FKHR cells. In contrast, CXCR7 highly expressed in RD becomes downregulated in RD/PAX3-FKHR cells. Next, promoter deletion and mutation studies revealed that whereas (a) expression of CXCR4 in RD and RD/PAX3-FKHR cells required nuclear respiratory factor-1 (NRF-1) binding site and (b) was additionally upregulated by direct interaction of NRF-1 with PAX3-FKHR, CXCR7 promoter activity required a proximal nuclear factor-kappaB-binding motif. The requirement of these factors for CXCR4 and CXCR7 promoter activities was additionally supported after blocking NRF-1 and nuclear factor-kappaB. Furthermore, CXCR4 expression in PAX3-FKHR(+) RMS cells seems to be enhanced because of the interaction of PAX3-FKHR and NRF-1 proteins in the proximal part of the promoter that prevents access of the negative regulator of transcription YY1 to its binding site. Finally, although hypoxia enhances CXCR4 and CXCR7 promoter activity and receptor expression in RD cells, it inhibits CXCR7 expression in RD/PAX3-FKHR cells. In conclusion, SDF-1 binding receptors CXCR4 and CXCR7 are differently regulated in RMS cells. The upregulation of CXCR4 and downregulation of CXCR7 expression by PAX3-FKHR or hypoxia may give SDF-1 an advantage to better engage the CXCR4 receptor, thus increasing RMS motility.

Human papillomavirus type 8 E2 protein unravels JunB/Fra-1 as an activator of the beta4-integrin gene in human keratinocytes.

The papillomavirus life cycle parallels keratinocyte differentiation in stratifying epithelia. We have previously shown that the human papillomavirus type 8 (HPV8) E2 protein downregulates beta4-integrin expression in normal human keratinocytes, which may trigger subsequent differentiation steps. Here, we demonstrate that the DNA binding domain of HPV8 E2 is sufficient to displace a cellular factor from the beta4-integrin promoter. We identified the E2-displaceable factor as activator protein 1 (AP-1), a heteromeric transcription factor with differentiation-specific expression in the epithelium. beta4-Integrin-positive epithelial cells displayed strong AP-1 binding activity. Both AP-1 binding activity and beta4-integrin expression were coregulated during keratinocyte differentiation suggesting the involvement of AP-1 in beta4-integrin expression. In normal human keratinocytes the AP-1 complex was composed of JunB and Fra-1 subunits. Chromatin immunoprecipitation assays confirmed that JunB/Fra-1 proteins interact in vivo with the beta4-integrin promoter and that JunB/Fra-1 promoter occupancy is reduced during keratinocyte differentiation as well as in HPV8 E2 positive keratinocytes. Ectopic expression of the tethered JunB/Fra-1 heterodimer in normal human keratinocytes activated the beta4-integrin promoter, while coexpression of HPV8 E2 reverted the JunB/Fra-1 effect. In summary, we identified a novel mechanism of human beta4-integrin regulation that is specifically targeted by the HPV8 E2 protein mimicking transcriptional conditions of differentiation. This may explain the early steps of how HPV8 commits its host cells to the differentiation process required for the viral life cycle.

The role of stromal-derived factor-1--CXCR7 axis in development and cancer.

Cancer metastasis is a major clinical problem that contributes to unsuccessful therapy. Augmenting evidence indicates that metastasizing cancer cells employ several mechanisms that are involved in developmental trafficking of normal stem cells. Stromal-derived factor-1 (SDF-1) is an important alpha-chemokine that binds to the G-protein-coupled seven-transmembrane span CXCR4. The SDF-1-CXCR4 axis regulates trafficking of normal and malignant cells. SDF-1 is an important chemoattractant for a variety of cells including hematopoietic stem/progenitor cells. For many years, it was believed that CXCR4 was the only receptor for SDF-1. However, several reports recently provided evidence that SDF-1 also binds to another seven-transmembrane span receptor called CXCR7, sharing this receptor with another chemokine family member called Interferon-inducible T-cell chemoattractant (I-TAC). Thus, with CXCR7 identified as a new receptor for SDF-1, the role of the SDF-1-CXCR4 axis in regulating several biological processes becomes more complex. Based on the available literature, this review addresses the biological significance of SDF-1's interaction with CXCR7, which may act as a kind of decoy or signaling receptor depending on cell type. Augmenting evidence suggests that CXCR7 is involved in several aspects of tumorogenesis and could become an important target for new anti-metastatic and anti-cancer drugs.