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In this double-blind, placebo-controlled, 52-week trial among postmenopausal women not receiving estrogen therapy, treatment with a patch delivering 300 μg of testosterone per day resulted in a significant although modest increase in the 4-week frequency of satisfying sexual episodes (1.4 more episodes per month), but the women were also subject to more adverse events, including androgenic side effects. In postmenopausal women not receiving estrogen therapy, treatment with a patch delivering 300 '1;g of testosterone per day resulted in a significant although modest increase in the 4-week frequency of satisfying sexual episodes. The literature suggests that the prevalence of sexual problems among women ranges from 9 to 43%. 1 – 4 Among these women, hypoactive sexual desire disorder is a commonly reported, symptom-driven condition characterized by a decrease or absence of interest in sexual activity, causing distress. 5 Decreased libido is common after natural menopause 6 , 7 and bilateral oophorectomy. 8 – 10 Several studies have shown the efficacy and short-term safety of a transdermal patch delivering 300 μg of testosterone per day for the treatment of hypoactive sexual desire disorder in women who have undergone either surgically induced or natural menopause and who use concomitant estrogen. 11 – . . .

Following WWII, the authoritarian and morally austere dictatorship of General Francisco Franco's Spain became the playground for millions of carefree tourists from Europe's prosperous democracies. This book chronicles how this helped to strengthen Franco's regime and economic and political standing.

The purpose of this randomized, double-masked, placebo-controlled study was to determine the efficacy and safety of risedronate in the prevention of vertebral fractures in postmenopausal women with established osteoporosis. The study was conducted at 80 study centers in Europe and Australia. Postmenopausal women (n= 1226) with two or more prevalent vertebral fractures received risedronate 2.5 or 5 mg/day or placebo; all subjects also received elemental calcium 1000 mg/day, and up to 500 IU/day vitamin D if baseline levels were low. The study duration was 3 years; however, the 2.5 mg group was discontinued by protocol amendment after 2 years. Lateral spinal radiographs were taken annually for assessment of vertebral fractures, and bone mineral density was measured by dual-energy X-ray absorptiometry at 6-month intervals. Risedronate 5 mg reduced the risk of new vertebral fractures by 49% over 3 years compared with control (p<0.001). A significant reduction of 61% was seen within the first year (p= 0.001). The fracture reduction with risedronate 2.5 mg was similar to that in the 5 mg group over 2 years. The risk of nonvertebral fractures was reduced by 33% compared with control over 3 years (p= 0.06). Risedronate significantly increased bone mineral density at the spine and hip within 6 months. The adverse-event profile of risedronate, including gastrointestinal adverse events, was similar to that of control. Risedronate 5 mg provides effective and well-tolerated therapy for severe postmenopausal osteoporosis, reducing the incidence of vertebral fractures and improving bone density in women with established disease.[PUBLICATION ABSTRACT]

Cancer of the small intestine represents less than two per cent of all the malignant tumors of the gastrointestinal tract. Because they are infrequent tumors, a review of a tumor registry was performed to analyze response to treatment of the disease and prognostic factors. A retrospective review of patients with primary cancer of the small intestine was performed using the Department of Defense Tumor Registry. The registry was accessed to determine stage, types of cancer, intervention, and patient outcomes. TNM staging and follow-up were available on 144 patients from 1970 to 1996. Median follow-up was 38.9 months. There were 92 (64%) males and 52 (38%) females. The median age was 55.7 years. The types of small intestinal cancer included 68 patients (47%) with adenocarcinoma, 41 patients (28%) with carcinoid, 18 patients (13%) with leiomyosarcoma, and 17 patients (12%) with lymphoma. The overall 5-year survival was 57 per cent and the median survival was 52 months. Survival of patients with adenocarcinoma was not dependent on location within the small bowel. Survival was best for early-stage tumors and when lesions could be completely resected.

BORIS (for brother of the regulator of imprinted sites), a paralogue of the transcription factor, CTCF, is a novel member of the cancer-testis antigen family. The aims of the present study were as follows: (1) to investigate BORIS expression in breast cells and tumours using immunohistochemical staining, western and real-time RT–PCR analyses and (2) assess potential correlation between BORIS levels in tumours with clinical/pathological parameters. BORIS was detected in all 18 inspected breast cell lines, but not in a primary normal breast cell culture. In 70.7% (41 of 58 cases) BORIS was observed in breast tumours. High levels of BORIS correlated with high levels of progesterone receptor (PR) and oestrogen receptor (ER). The link between BORIS and PR/ER was further confirmed by the ability of BORIS to activate the promoters of the PR and ER genes in the reporter assays. Detection of BORIS in a high proportion of breast cancer patients implies potential practical applications of BORIS as a molecular biomarker of breast cancer. This may be important for diagnosis of the condition and for the therapeutic use of BORIS. The ability of BORIS to activate promoters of the RP and ER genes points towards possible involvement of BORIS in the establishment, progression and maintenance of breast tumours.

BackgroundAn increasing body of evidence suggests that in addition to the type, density, and state of immune cells in the tumor microenvironment (TME), also their proximity to cancer cells influences immunotherapy outcome. For example, favorable responses to immune checkpoint inhibitors in melanoma are associated with higher densities of CD8+ tumor-infiltrating lymphocytes (TIL) within 20 μm distance of melanoma cells. This notion is in line with the understanding that upon specific antigen recognition, cytotoxic T cells physically engage with their target cells through their TCRs followed by immunological synapse formation. Indeed, structural and functional avidity of cytotoxic CD8+ T cells correlates strongly with their activity against cancer cells. Together, these observations point to the importance of direct interactions between cytotoxic T cells and tumor cells in the TME. This led us to investigate whether tumor-specific CD8+ T cells can be isolated from clinical cancer specimens as heterotypic clusters.Materials and MethodsWe employed a tumor cell-T cell co-culture in vitro model, patient samples and ex vivo assays. To evaluate functional interactions between human T cells and tumor cells, we made use of a system we engineered previously, comprising melanoma cells expressing both HLA-A*02:01 and the MART-1 tumor antigen. They were challenged with CD8+ T cells from PBMCs that were retrovirally transduced with a MART-1-specific TCR. To asses these interactions in patient material, upon surgical removal tissue was cut into small fragments, digested and analyzed by (image-based) flow cytometry. Interacting (cluster) and not-interacting (singlets) T cells were isolated and expanded in vitro. To characterize tumor cell:T cell interactions single cell TCR and RNA sequencing is used, as well as ex vivo co-cultures with autologous tumor cells.ResultsWe found that in defined co-cultures, tumor antigen-recognizing T cells were commonly enriched over non-specific T cells in heterotypic clusters with tumor cells, prompting us to investigate whether such specific clusters could be isolated also from cancer specimens. We observed that from 10/10 human melanoma metastases, we were able to isolate heterotypic clusters, comprising CD8+ T cells interacting with one or more tumor cells and/or antigen-presenting cells (APCs), which was validated by imaging flow cytometry. Upon expansion, CD8+ T cells from tumor cell clusters and APC clusters exerted on average 7.6-fold increased melanoma-killing activity over T cell singlets, which was associated with enhanced cytokine production. CD8+ T cells from clusters were enriched for tumor-reactive and exhausted gene signatures. Integration with T cell receptor (TCR)-sequencing showed increased clonality of clustered T cells, indicative of expansion upon antigen recognition.ConclusionsTogether, these results demonstrate that tumor-reactive CD8+ T cells are enriched in functional clusters with tumor cells and/or APCs, and that they can be isolated and expanded from clinical samples. Being often excluded in cell sorting procedures, these distinct heterotypic CD8+ T cell clusters serve as a valuable source amenable to deciphering functional tumor-immune cell interactions, while they may also be therapeutically explored. S. Ibáñez Molero: E. Ownership Interest (stock, stock options, patent or other intellectual property); Modest; P097110NL. J. Veldman: E. Ownership Interest (stock, stock options, patent or other intellectual property); Modest; P097110NL. J. J H Traets: None. A. George: None. K. Hoefakker: None. S. Pack: None. L. Tas: None. P. Alóndiga-Mérida: None. B. van den Broek: None. R. Harkes: None. M. Nieuwland: None. M. van Baalen: None. E. Mul: None. S. Tol: None. J.B.A.G. Haanen: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; Amgen, Asher Bio, BioNTech, BMS, MSD, Novartis, Sastra Cell Therapy. E. Ownership Interest (stock, stock options, patent or other intellectual property); Modest; Neogene Tx. F. Consultant/Advisory Board; Modest; BMS, CureVac, GSK, Imcyse, Iovance Bio, Instil Bio, Immunocore, Ipsen, Merck Serono, MSD, Molecular Partners, Novartis, Pfizer, Roche/Genentech, Sanofi, Scenic, Third Rock Ventures, Achilles Tx, BioNTech US, Instil Bio, PokeAcell, T-Knife, Scenic, Neogene Therapeutics. W.J.V. Houdt: None. D.S. Peeper: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; Oncode Institute, Dutch Cancer Society KWF. E. Ownership Interest (stock, stock options, patent or other intellectual property); Modest; P097110NL, Immagene. F. Consultant/Advisory Board; Modest; Immagene.

As a result of the increasing use of genome wide telomere screening, it has become evident that a significant proportion of people with idiopathic mental retardation have subtle abnormalities involving the telomeres of human chromosomes. However, during the course of these studies, there have also been telomeric imbalances identified in normal people that are not associated with any apparent phenotype. We have begun to scrutinise cases from both of these groups by determining the extent of the duplication or deletion associated with the imbalance. Five cases were examined where the telomere rearrangement resulted in trisomy for the 16p telomere. The size of the trisomic segment ranged from ∼4-7 Mb and the phenotype included mental and growth retardation, brain malformations, heart defects, cleft palate, pancreatic insufficiency, genitourinary abnormalities, and dysmorphic features. Three cases with telomeric deletions without apparent phenotypic effects were also examined, one from 10q and two from 17p. All three deletions were inherited from a phenotypically normal parent carrying the same deletion, thus without apparent phenotypic effect. The largest deletion among these cases was ∼600 kb on 17p. Similar studies are necessary for all telomeric regions to differentiate between those telomeric rearrangements that are pathogenic and those that are benign variants. Towards this goal, we are developing “molecular rulers” that incorporate multiple clones at each telomere that span the most distal 5 Mb region. While telomere screening has enabled the identification of telomere rearrangements, the use of molecular rulers will allow better phenotype prediction and prognosis related to these findings.

Carney complex (CNC) is a multiple neoplasia syndrome characterized by spotty skin pigmentation, cardiac and other myxomas, endocrine tumours and psammomatous melanotic schwannomas 1 , 2 , 3 , 4 , 5 . CNC is inherited as an autosomal dominant trait and the genes responsible have been mapped to 2p16 and 17q22–24 (refs 6 , 7 ). Because of its similarities to the McCune-Albright syndrome 5 , 8 and other features, such as paradoxical responses to endocrine signals 9 , genes implicated in cyclic nucleotide-dependent signalling have been considered candidates for causing CNC (ref. 10 ). In CNC families mapping to 17q, we detected loss of heterozygosity (LOH) in the vicinity of the gene ( PRKAR1A ) encoding protein kinase A regulatory subunit 1-α (RIα), including a polymorphic site within its 5′ region. We subsequently identified three unrelated kindreds with an identical mutation in the coding region of PRKAR1A . Analysis of additional cases revealed the same mutation in a sporadic case of CNC, and different mutations in three other families, including one with isolated inherited cardiac myxomas. Analysis of PKA activity in CNC tumours demonstrated a decreased basal activity, but an increase in cAMP-stimulated activity compared with non-CNC tumours. We conclude that germline mutations in PRKAR1A , an apparent tumour-suppressor gene, are responsible for the CNC phenotype in a subset of patients with this disease.