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1.
Artigo em Inglês | MEDLINE | ID: mdl-33538861

RESUMO

Owing to their key role in several diseases including cancer, activating and inhibitory immune checkpoint molecules are increasingly exploited as targets for immunotherapy. Recently, we demonstrated that platelets, which largely influence tumor progression and immune evasion, functionally express the ligand of the checkpoint molecule GITR. This immunoreceptor modulates effector functions of T cells and NK cells with its function varying dependent on cellular context and activation state. Here, we provide a comparative analysis of platelet-derived GITRL (pGITRL) in breast cancer patients and healthy volunteers. The levels of pGITRL were found to be higher on platelets derived from cancer patients and appeared to be specifically regulated during tumor progression as exemplified by several clinical parameters including tumor stage/grade, the occurrence of metastases and tumor proliferation (Ki67) index. In addition, we report that pGITRL is upregulated during platelet maturation and particularly induced upon exposure to tumor-derived soluble factors. Our data indicate that platelets modulate the GITR/GITRL immune checkpoint in the context of malignant disease and provide a rationale to further study the GITR/GITRL axis for exploitation for immunotherapeutic intervention in cancer patients.

2.
Mol Oncol ; 2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33476079

RESUMO

Chemotherapy (CTX) remains the standard of care for most aggressive tumours, including breast cancer (BC). In BC chemotherapeutic regimens, the maximum tolerated dose of cytotoxic drugs is administered at regular intervals, and cancer cells can re-grow or adapt during the resting periods between cycles. The impact of the tumour microenvironment on the fate of cancer cells after CTX remains poorly understood. Here, we show that paracrine signalling from CTX-treated cancer cells to stromal fibroblasts can drive cancer cell recovery after cytotoxic drug withdrawal. Interferon ß1 (IFNß1) secreted by cancer cells following treatment with high doses of CTX instigates the acquisition of an anti-viral state in stromal fibroblasts. This state is associated with an expression pattern here referred to as interferon signature (IFNS), which encompasses several interferon-stimulated genes (ISGs), including numerous pro-inflammatory cytokine genes. This crosstalk is an important driver of the expansion of BC cells after CTX, and IFNß1 blockade in tumour cells abrogated their fibroblast-dependent recovery potential. Analysis of human breast carcinomas supported a link between CTX-induced IFNS in tumour stroma and poor response to CTX treatment. First, IFNß1 expression in human breast carcinomas was found to inversely correlate with recurrence free survival (RFS). Second, using laser capture microdissection data sets, we show a higher expression of IFNS in the stromal tumour compartment compared to the epithelial one and this signature was found to be more prominent in more aggressive subtypes of BC (basal-like), pointing to a pro-tumorigenic role of this signature. Moreover, IFNS was associated with higher recurrence rates and a worse outcome in BC patients. Our study unravels a novel form of paracrine communication between cancer cells and fibroblasts that ultimately results in CTX resistance. Targeting this axis has the potential to improve CTX outcomes in patients with BC.

3.
Am J Hum Genet ; 108(2): 337-345, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33434492

RESUMO

Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is associated with congenital absence of the uterus, cervix, and the upper part of the vagina; it is a sex-limited trait. Disrupted development of the Müllerian ducts (MD)/Wölffian ducts (WD) through multifactorial mechanisms has been proposed to underlie MRKHS. In this study, exome sequencing (ES) was performed on a Chinese discovery cohort (442 affected subjects and 941 female control subjects) and a replication MRKHS cohort (150 affected subjects of mixed ethnicity from North America, South America, and Europe). Phenotypic follow-up of the female reproductive system was performed on an additional cohort of PAX8-associated congenital hypothyroidism (CH) (n = 5, Chinese). By analyzing 19 candidate genes essential for MD/WD development, we identified 12 likely gene-disrupting (LGD) variants in 7 genes: PAX8 (n = 4), BMP4 (n = 2), BMP7 (n = 2), TBX6 (n = 1), HOXA10 (n = 1), EMX2 (n = 1), and WNT9B (n = 1), while LGD variants in these genes were not detected in control samples (p = 1.27E-06). Interestingly, a sex-limited penetrance with paternal inheritance was observed in multiple families. One additional PAX8 LGD variant from the replication cohort and two missense variants from both cohorts were revealed to cause loss-of-function of the protein. From the PAX8-associated CH cohort, we identified one individual presenting a syndromic condition characterized by CH and MRKHS (CH-MRKHS). Our study demonstrates the comprehensive utilization of knowledge from developmental biology toward elucidating genetic perturbations, i.e., rare pathogenic alleles involving the same loci, contributing to human birth defects.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/genética , Anormalidades Congênitas/genética , Ductos Paramesonéfricos/anormalidades , Ductos Paramesonéfricos/crescimento & desenvolvimento , Mutação , Ductos Mesonéfricos/crescimento & desenvolvimento , Adulto , Proteína Morfogenética Óssea 4/genética , Proteína Morfogenética Óssea 7/genética , Códon sem Sentido , Feminino , Estudos de Associação Genética , Pleiotropia Genética , Proteínas Homeobox A10/genética , Proteínas de Homeodomínio/genética , Humanos , Fator de Transcrição PAX8/genética , Herança Paterna , Penetrância , Proteínas com Domínio T/genética , Fatores de Transcrição/genética , Proteínas Wnt/genética , Ductos Mesonéfricos/anormalidades
4.
Front Cell Dev Biol ; 8: 572281, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33072755

RESUMO

The Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome (OMIM 277000) is characterized by agenesis of the uterus and upper part of the vagina in females with normal ovarian function. While genetic causes have been identified for a small subset of patients and epigenetic mechanisms presumably contribute to the pathogenic unfolding, too, the etiology of the syndrome has remained largely enigmatic. A comprehensive understanding of gene activity in the context of the disease is crucial to identify etiological components and their potential interplay. So far, this understanding is lacking, primarily due to the scarcity of samples and suitable tissue. In order to close this gap, we profiled endometrial tissue of uterus rudiments in a large cohort of MRKH patients using RNA-seq and thereby provide a genome-wide view on the altered transcription landscape of the MRKH syndrome. Differential and co-expression analyses of the data identified cellular processes and candidate genes that converge on a core network of interconnected regulators that emerge as pivotal for the perturbed expression space. With these results and browsable access to the rich data through an online tool we seek to accelerate research to unravel the underlying biology of the syndrome.

5.
Oncotarget ; 11(35): 3279-3285, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32934773

RESUMO

PURPOSE: High throughput panel sequencing to tailor therapy in precision oncology promises to improve outcome in patients with metastatic breast cancer. However, data that clearly show any benefit from such an approach is still pending. MATERIALS AND METHODS: We performed a retrospective analysis of advanced breast cancer patients that underwent panel sequencing for suggestion of target related drugs. We aimed to (i) determine the frequency of actionable mutations per patient and to (ii) assess the clinical impact of results on treatment options. RESULTS: A total of 52 patients underwent panel sequencing of archived tumor tissue. Every sample showed at least one affected gene, accounting for actionable mutations in 45 of 52 patients (87%). New treatment options that would not have been used as indicated by standard predictive markers (such as hormonal receptor status or HER2-status) were found in 22 of 52 patients (42%). We detected therapeutic relevant pathogenic germline variants in 9,6% (5/52) of the patients. CONCLUSIONS: Using a high throughput-panel sequencing approach to identify actionable mutations in patients with metastatic breast cancer, we identified potential target-related treatment options in a large proportion of our patients, some of which would not have been considered without this data. Prospective clinical trials with compounds targeting the identified actionable mutations are needed to determine which treatments can indeed improve survival or quality of life by limiting exposure to ineffective drugs in advanced breast cancer.

6.
Wien Med Wochenschr ; 2020 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-32757107

RESUMO

Atypical vascular proliferations (AVP) are a late complication after radiotherapy. Most cases have been reported in female breast cancer patients on the chest wall. These lesions are mostly of the lymphatic type. Herein, we report a blood vascular-type AVP in a male on the neck 60 years after radiotherapy for a benign hemangioma, which makes this case exceptional. We removed the whole chronic radiodermatitis surgically. Histopathology excluded vascular malignancies but confirmed AVP. We discuss the differential diagnoses and treatment.

7.
R Soc Open Sci ; 7(5): 200092, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32537217

RESUMO

In the light of recent phylogenetic studies, we re-assess the taxonomy and biogeography of the Varanus populations distributed in the Micronesian islands of Palau, the Western Carolines and the Marianas. Whether these populations are of natural origin or human introductions has long been contentious, but no study has fully resolved that question. Here, we present molecular and morphological evidence that monitor lizards of the Varanus indicus Group reached both Palau and the Mariana Islands sometime in the late Pleistocene and subsequently differentiated into two separate species endemic to each geographical region. One species is confined to the Mariana Islands, and for these populations, we revalidate the name V. tsukamotoi Kishida, 1929. The other species has a disjunct distribution in Palau, the Western Carolines and Sarigan Island in the Northern Marianas and is herein described as V. bennetti sp. nov. Both species are most closely allied to each other, V. lirungensis and V. rainerguentheri, suggesting that colonization of Micronesia took place from the Moluccas. We discuss the biogeographic distributions of both species in the light of the likely colonization mechanism and previous arguments for human introduction, and we argue that bounties for Palauan populations are ill-advised and plans for eradication of some other populations must first demonstrate that they are, in fact, introduced and not native.

8.
Dermatol Ther ; : e13877, 2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32558202

RESUMO

Hidradenitis suppurativa/acne inversa (HS/AI) is one of the most debilitating dermatoses with a strong negative impact on every dimension of quality of life. Treatment is dependent on the severity of clinical manifestations and comorbidities. While anti-inflammatory and antimicrobial approaches are recommended for mild and moderate stages, immunomodulatory drugs have gained increasing interest in all stages of HS/AI. We reviewed the available data on this subject in a narrative review and included not only substances with published final outcome but those where either the ongoing trials or experience from case report. Furthermore, we investigated combined surgical therapy and immunomodulatory drugs and raised specific questions to be answered in controlled settings. This aspect seems to be underrepresented. The first approved medical treatment for HS/AI is adalimumab. Other cytokine, interleukin, Janus kinase and C5a inhibitors and antagonists are under investigation. IL-1 inhibitors and antagonists may become an option for mild to moderate HS/AI, while most of the other medical compounds target moderate to severe HS/AI. Despite medical efforts with immunomodulatory agents, surgery remains a cornerstone of efficient HS/AI therapy. Better outcome in advanced disease might be achieved by combining drug therapy and surgery, but more systematic clinical trials are necessary for the optimal combination.

10.
Dermatol Ther ; 33(4): e13675, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32447821

RESUMO

Merkel cell carcinoma (MCC) is a rare but aggressive non-melanoma skin cancer with significant morbidity and mortality. Treatment of choice for primary and locoregional MCC is complete surgical removal with sentinel lymphonodectomy and postsurgical radiotherapy of tumor basin and locoregional lymph nodes. In nonresectable and advanced tumors, drug therapy is indicated. While cytotoxic chemotherapy has resulted in higher response rates, overall survival remained nearly unaffected. With a better insight into tumor development and biology, new treatment s became available. Immune checkpoint inhibitors result in durable responses with a better safety profile that classical combined chemotherapy. Combinations of immune checkpoint inhibitors with and without radiotherapy help to overcome acquired drug-resistance. New compounds for vaccination and oral use are on the horizon. Despite all progress, treatment of MCC remains a challenge that needs close interdisciplinary teamwork.

11.
Cancers (Basel) ; 12(4)2020 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-32340164

RESUMO

Cold atmospheric plasma (CAP) treatment is developing as a promising option for local anti-neoplastic treatment of dysplastic lesions and early intraepithelial cancer. Currently, high-frequency electrosurgical argon plasma sources are available and well established for clinical use. In this study, we investigated the effects of treatment with a non-thermally operated electrosurgical argon plasma source, a Martin Argon Plasma Beamer System (MABS), on cell proliferation and metabolism of a tissue panel of human cervical cancer cell lines as well as on non-cancerous primary cells of the cervix uteri. Similar to conventional CAP sources, we were able to show that MABS was capable of causing antiproliferative and cytotoxic effects on cervical squamous cell and adenocarcinoma as well as on non-neoplastic cervical tissue cells due to the generation of reactive species. Notably, neoplastic cells were more sensitive to the MABS treatment, suggesting a promising new and non-invasive application for in vivo treatment of precancerous and cancerous cervical lesions with non-thermally operated electrosurgical argon plasma sources.

12.
Zootaxa ; 4747(2): zootaxa.4747.2.3, 2020 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-32230109

RESUMO

Currently three different species are recognized within the Southeast Asian agamid genus Hydrosaurus: H. amboinensis (Schlosser, 1768) from Ambon, Seram, Sulawesi and New Guinea, H. pustulatus (Eschscholtz, 1829) from the Philippines and H. weberi Barbour, 1911 from Halmahera and adjacent islands. Historically, two additional species were described from the island of Sulawesi, but were synonymized with H. amboinensis more than a century ago and have been treated as such in most subsequent publications. In order to revise the taxonomy and diversity of these enigmatic agamid lizards, we examined the corresponding type specimens and additional material originating from Sulawesi and compared them to photographs of live specimens from field trips. Due to differences in colour pattern and scalation characters, we resurrect the taxa celebensis Peters, 1872 and microlophus Bleeker, 1860 from the synonymy of H. amboinensis, which in turn is restricted to the central Moluccas and New Guinea. Hence, Sulawesi is currently the only known island within the genus' range to be inhabited by two different species of sailfin lizards. Our systematic investigation brings the number of recognized species within the genus Hydrosaurus to five.


Assuntos
Lagartos , Animais , Indonésia
13.
Zootaxa ; 4743(1): zootaxa.4743.1.5, 2020 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-32230352

RESUMO

We provide a detailed redescription of the two original type specimens of the little-known, endemic Andaman water monitor, Varanus salvator andamanensis Deraniyagala, 1944. Examination of further voucher specimens allows for an expanded morphological diagnosis of this island taxon and comparison with other currently recognized subspecies of the wide-spread Southeast Asian water monitor. Based on the specimens examined, V. s andamanensis is characterized by a homogenous black dorsal background colour, with five to seven, more or less distinctive transverse rows of small spots or ocelli, light yellowish dots arranged sporadically between transverse spot/ocelli rows on the body, light yellowish coloured spots distributed sporadically throughout both forelimbs and hind limbs; 17-18 prominent rows of light spots continuing from base of tail to its tip dorsally with sporadically arranged dots on lateral sides of tail; and higher scale counts in transverse dorsal scale rows. Based on photographic evidence and examination of museum specimens, V. s. andamanensis inhabits both the Andaman and southern Nicobar Islands, which politically belong to the Republic of India. In addition, we confirm the presence of V. s. macromaculatus in the northern and central Nicobar Islands, thus providing evidence for the allopatric co-occurrence of two different water monitor subspecies in these remote archipelagos.


Assuntos
Lagartos , Animais , Ilhas
15.
Mol Nutr Food Res ; 64(7): e1900390, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31976617

RESUMO

SCOPE: Urolithin A (UA) is a gut-derived bacterial metabolite from ellagic acid found in pomegranates, berries, and nuts can downregulate cell proliferation and migration. Cell proliferation and cell motility require actin reorganization, which is under control of ras-related C3 botulinum toxin substrate 1 (Rac1) and p21 protein-activated kinase 1 (PAK1). The present study explores whether UA can modify actin cytoskeleton in cancer cells. METHODS: The effect of UA on globular over filamentous actin ratio is determined utilizing Western blotting, immunofluorescence, and flow cytometry. Rac1 and PAK1 levels are measured by quantitative RT-PCR and immunoblotting. As a result, a 24 h treatment with UA (20 µm) significantly decreased Rac1 and PAK1 transcript levels and activity, depolymerized actin and wound healing. The effect of UA on actin polymerization is mimicked by pharmacological inhibition of Rac1 and PAK1. The effect is also mirrored by knock down using siRNA. CONCLUSION: UA leads to disruption of Rac1 and Pak1 activity with subsequent actin depolymerization and migration. Thus, use of dietary UA in cancer prevention or as adjuvant therapy is promising.

16.
Cancers (Basel) ; 12(2)2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31979067

RESUMO

Non-invasive physical plasma (NIPP) generated by non-thermally operated electrosurgical argon plasma sources is a promising treatment for local chronic inflammatory, precancerous and cancerous diseases. NIPP-enabling plasma sources are highly available and medically approved. The purpose of this study is the investigation of the effects of non-thermal NIPP on cancer cell proliferation, viability and apoptosis and the identification of the underlying biochemical and molecular modes of action. For this, cervical cancer (CC) single cells and healthy human cervical tissue were analyzed by cell counting, caspase activity assays, microscopic and flow-cytometric viability measurements and molecular tissue characterization using Raman imaging. NIPP treatment caused an immediate and persisting decrease in CC cell growth and cell viability associated with significant plasma-dependent effects on lipid structures. These effects could also be identified in primary cells from healthy cervical tissue and could be traced into the basal cell layer of superficially NIPP-treated cervical mucosa. This study shows that NIPP treatment with non-thermally operated electrosurgical argon plasma devices is a promising method for the treatment of human mucosa, inducing specific molecular changes in cells.

17.
Open Access Maced J Med Sci ; 7(18): 2976-2978, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31850102

RESUMO

BACKGROUND: Cutaneous angiosarcoma of the head and neck region is a subtype of cutaneous angiosarcoma with an unfavourable prognosis. Diagnosis is often delayed. PATENTS AND METHODS: The setting is an Academic Teaching Hospital Skin Cancer Center. Eight Caucasian patients could be identified, 5 men and 3 women. Delay to diagnosis was between 12 to 4 months (mean 7.8 ± 2.9 months). The diagnosis was confirmed in all cases by histopathology and immunohistochemistry. Hematoxylin-eosin, Giemsa, PAS, iron and reticulin stains were performed. Endothelial markers such as CD31, CD34, and Ki67 for proliferation assessment were used in all tumours. Other markers used included pan-cytokeratin (CK), CK7, CK20, ERG, CD 40 and c-MYC. Tumours were classified as localised versus multifocal or diffuse form. Tumour staging was performed according to the 8th edition of the AJCC. The mean age of patients was 79 years ± 26.4 years. The male to female ratio was 1.7. Tumour classification was diffuse in 2 patients, multilocular in one and localised in 5 patients. In 5 of 8 patients, a multimodal treatment was performed, one had radiotherapy alone, in another patient surgery was performed, and radiotherapy is planned. The mean OS was 26.4 months ± 24.5 months. CONCLUSION: Cutaneous angiosarcoma of the head and neck is an aggressive tumour with a poor prognosis. Although surgery remains a cornerstone of treatment, the tumour size at first presentation may be too large, and the elderly patients maybe not suitable for extensive surgery. Therefore, multimodal treatment with adjuvant radiotherapy and/ or chemotherapy is necessary. Multimodal treatment offers a better outcome than radiotherapy or chemotherapy alone. Stealth liposomal encapsulated doxorubicin is a therapeutic option for elderly patients with improved safety compared to conventional doxorubicin.

18.
Open Access Maced J Med Sci ; 7(18): 3006-3008, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31850110

RESUMO

BACKGROUND: Cutaneous B-cell lymphomas represent about 25% of all cutaneous lymphomas. Peripheral diffuse large B-cell lymphoma of the leg type is the most aggressive subtype seen mainly in elderly patients. Treatment is not standardised. CASE REPORT: An 87-year-old female patient was presented in May 2018 because of the development of painless subcutaneous nodules on the legs since late 2017. On examination, we observed up to 5 cm large erythematous nodules on the legs and a smaller plaque in the left submammary fold. The histology of a skin demonstrated tumour infiltrate that was separated from the overlying epidermis by a grenz zone. It consisted of densely packed, blastoid lymphocytic cells with numerous, and some atypical mitoses. The cells were positive for CD20, CD79A and CD5. Almost 100% of the cells were labelled with Ki67. The diagnosis of a diffuse large B-cell lymphoma (PCLBCL-LT) of the leg was confirmed. Histologic analysis of a bone marrow biopsy demonstrated a hypercellular bone marrow without malignant lymphatic infiltrates. Diagnostic ultrasound of cervical nodes and computerised tomography (CT) scans (native and with contrast medium) of head, neck and trunk excluded an extracutaneous manifestation of the PCLBCL-LT. Treatment with rituximab plus bendamustibe was initiated, but tumour progress was noted after the second course. Suggested palliative therapy with radiation and rituximab was refused. The patient died 7 months after diagnosis. CONCLUSIONS: Although some trials suggested a beneficial effect of immuno-chemotherapy, the prognosis of (PCLBCL-LT) remains poor. Standardised treatment is missing due to the relative rarity of this malignancy.

19.
Open Access Maced J Med Sci ; 7(18): 3009-3012, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31850111

RESUMO

BACKGROUND: Measles is highly contagious and is caused by the RNA morbillivirus. The best protection is active immunisation in early childhood. Without immunisation morbidity and mortality of measles are high. In recent years, an increasing number of adult measles has been recognised in Europe. CASE REPORTS: We report here on two adult patients - a 40-year-old male and a 55-year-old female - who presented with fever, fatigue, cough, coryza, conjunctivitis and maculopapular rash. The suspicion of adult measles infection was confirmed by positivity for IgM antibodies against measles virus and reverse-transcriptase polymerase chain reaction in blood and urine. Patients were isolated, and the treatment was symptomatic. In the younger patient, complete recovery was achieved within two weeks. In the older patient, an acute encephalopathy developed after initial improvement characterised by cognitive impairment. CONCLUSIONS: In patients presenting with fever and maculopapular rash and fatigue, measles should be considered even in adult patients. Early diagnosis with subsequent isolation and registration of patients are important measures to prevent local outbreaks of the disease.

20.
Open Access Maced J Med Sci ; 7(18): 3026-3029, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31850115

RESUMO

BACKGROUND: Reed syndrome or multiple cutaneous leiomyomas with uterine leiomyomas are part of the spectrum of heterozygous hereditary disorders with cutaneous, genital and renal manifestations. CASE REPORTS: We report two female cases of multiple cutaneous leiomyomas with uterine leiomyomas (MCUL) without renal disease, in particular without cysts or papillary renal carcinoma, aged 52 and 55 years, respectively. The diagnosis of pilar leiomyomas was confirmed by histology and immunostaining for smooth muscle actin and desmin. Both females had a hysterectomy in the past because of uterus myomatosus. In one patient, a new mutation of the FH gene was detected, i.e. a heterozygote c1300_1301del (p.Cys434Argfs17) mutation in the exon 9 of the FH gene. CONCLUSION: Since MCUL shares features with the genetic cancer syndrome hereditary leiomyomatosis and renal cell carcinoma (HLRCC), these patients need a regular follow-up to prevent the late diagnosis of renal cancer.

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