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Ateles utilizes one of the largest community ranges in the Americas. Large ranges ate necessary due to Ateles' high frugivory and the patchy, unpredictable nature of fruiting. Elimination of hall of a community's range could be detrimental to Ateles' survival. Such a situation exists within the Large forest at Estacion Biologica La Suerte, Costa Rica (EBLS). The EBLS forest (100 Ha) is divided into the 30 Ha Large Forest (LF), owned and managed by EBLS and the privately owned 70 Ha German Forest (GF) which is currently being logged intensively. This study compares Pruetz's (2000) baseline demographic data on A. geoffroyi with data collected since logging began. Line transect surveys were conducted over established trails within the LF and GF on a community of Ateles geoffroyi. Data were collected on group size, composition, diet, activity, and ranging, and then compared to Pruetz's (2000) baseline data. Results are comparable to Pruetz's data, with slight increases in mean subgroup size and overall population density. Mean subgroup size was 3.18 with a range of 1-8. Mode subgroup size was 2. At least 1 adult female was observed in 76% of subgroups. Male-only subgroups were observed 12% and solitary animals 5% of total observations. Minimum population size was 13 individuals. Population density estimated is at 13-18 individuals/k[m.sup.2]. Initial results suggest deforestation in greater than one-half of A. geoffroyi's possible range has had little effect on their demography and ranging patterns. However, deforestation is only in its first stages and further logging may well impact Ateles survival.

Studies of primate foraging and ranging behavior indicate evidence of goal-directed travel and relatively straight-line movement between sequential feeding sites. In the case of mantled howlers (Alouatta palliata) on BCI, Panama, Milton (1980) has argued that group members center their feeding, resting, and ranging activities on a small set of pivotal trees that are visited several times daily. The degree to which this pattern is adopted by mantled howlers at other sites remains unclear. In this study we present quantitative data on travel routes taken by mantled howlers and address questions concerning howler goal-directed travel and spatial mapping. Data were collected during July and August of 2002 on a group of A. palliata inhabiting a dry tropical forest on Isla de Ometepe, Nicaragua. Over the course of 15 days and 104 hours of observation, all trees the howlers were observed to travel, feed, and rest in were marked (N=299), and distances and angles between trees were measured and mapped. Travel routes were identified by following a focal individual for 6-8 hours per day. During the course of our study, howlers traveled between 185.5 to 659.5 meters per day. An analysis indicates that whereas 5 paths were reused frequently and accounted for 33% (37/111) of all travel route segments, 43% (48/111) of route segments were used only on one or two occasions. The results suggest that travel in Nicaraguan mantled howlers is characterized by evidence of both route-based travel and the use of varied pathways to reach previously visited feeding and resting sites. Additional relationships between mantled howler ranging, activity patterns, and use of spatial information are discussed.

Objective/hypothesis: Most methods to measure phonation threshold pressure (PTP) are clinically impractical because they are invasive. This report concerns an airflow interruption system developed to allow noninvasive estimation of (PTP) at different levels of vocal intensity. An estimation of PTP was made for normal subjects with normal larynges and no voice complaints and for individuals who had dysphonia associated with vocal polyps to compare the estimated minimal pressure across the glottis that was required to sustain phonation in the two conditions.Study Design: This was a methodological study designed to measure an unanticipated PTP from a subject.Methods: Subjects sustained a constant tone and the airflow was directed into a section of pipe with an airtight mask over the mouth and nose. The airflow, intramask pressure, and intensity of the acoustic output were recorded. A PTP was predicted from a difference between an estimate of the subglottal pressure and the vocal tract pressure at the point that phonation ceased after interruption of airflow. Eleven control subjects and 13 patients with vocal fold polyps were studied. In each population there were eight men and five women. The individuals in the group with vocal fold polyps averaged 39 years of age, and the control subject group averaged 49 years of age. Normal subjects produced a steady vowel /a/ at 75, 80, and 85 dB. Patients with polyps were unable to sustain phonation at these levels but were able to produce phonation at 65, 70, and 75 dB. The validity of the system was tested using a laryngeal model and in a patient with a normal larynx and voice who had a tracheotomy (placed for sleep apnea syndrome) which allowed direct measurement of subglottal pressure.Results: The measured mean PTP levels (with standard deviation [SD]) for the control subjects were 2.38 (1.273), 2.67 (1.879), and 2.98 (2.23) cm H2O at 75, 80, and 85 dB, respectively. The measured mean PTP levels (with SD) for the patients with polyps were 4.79 (2.67), 5.85 (2.34), and 7.37 (3.26) cm H2O at 75, 80, and 85 dB, respectively. The differences in mean PTP between groups at 75, 80, and 85 dB were significant at P = .013, P = .017, and P = .010, respectively.Conclusions: The estimations of PTP for patients with vocal fold polyps were significantly higher than for the control subjects at three phonation levels. [ABSTRACT FROM AUTHOR]

Background: The American Cancer Society recommends physicians inform average-risk women about endometrial cancer risk on reaching menopause, but new diagnoses are rising fastest in women aged younger than 50 years. Educating these younger women about endometrial cancer risks requires knowledge of risk factors. However, endometrial cancer in young women is rare and challenging to study in single study populations., Methods: We included 13 846 incident endometrial cancer patients (1639 aged younger than 50 years) and 30 569 matched control individuals from the Epidemiology of Endometrial Cancer Consortium. We used generalized linear models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for 6 risk factors and endometrial cancer risk. We created a risk score to evaluate the combined associations and population attributable fractions for these factors., Results: In younger and older women, we observed positive associations with body mass index and diabetes and inverse associations with age at menarche, oral contraceptive use, and parity. Current smoking was associated with reduced risk only in women aged 50 years and older (Phet < .01). Body mass index was the strongest risk factor (OR≥35 vs<25 kg/m2 = 5.57, 95% CI = 4.33 to 7.16, for ages younger than 50 years; OR≥35 vs<25 kg/m2 = 4.68, 95% CI = 4.30 to 5.09, for ages 50 years and older; Phet = .14). Possessing at least 4 risk factors was associated with approximately ninefold increased risk in women aged younger than 50 years and approximately fourfold increased risk in women aged 50 years and older (Phet < .01). Together, 59.1% of endometrial cancer in women aged younger than 50 years and 55.6% in women aged 50 years and older were attributable to these factors., Conclusions: Our data confirm younger and older women share common endometrial cancer risk factors. Early educational efforts centered on these factors may help mitigate the rising endometrial cancer burden in young women., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Endometrial cancer is one of the few cancers for which mortality is still increasing. A lack of treatment options remains a major challenge, particularly for some subtypes of the disease. GZD824, also known as olverembatinib, is a multi-kinase inhibitor previously investigated in clinical trials for chronic myeloid leukaemia and Ph+ acute lymphoblastic leukaemia as a BCR-ABL inhibitor. This study aimed to investigate the pre-clinical efficacy of GZD824 for the treatment of EC., Methods: Here, we undertook pre-clinical evaluation of GZD824 in seven endometrial cancer cell lines (HEC-1-A, HEC-1-B, MFE296, RL95-2, Ishikawa, KLE and ARK-1), one normal immortalised endometrium derived cell line (E6E7hTERT) and primary mesothelial and fibroblast cells isolated from normal omentum samples., Results: GZD824 inhibited the proliferation of all endometrial cancer cell lines, which were significantly more sensitive to GZD824 compared to normal cells (p = 0.030). GZD824 significantly inhibited migration in Ishikawa (endometrioid) and ARK1 (serous) endometrial cancer cell lines and significantly inhibited invasion in the ARK1 cells. Whole transcriptome regulation following two doses (0.1 and 1 μM) of GZD824 in Ishikawa and ARK1 cells was investigated via RNA-seq, and key components of enriched pathways were investigated at the translational level. Key pathways altered included ROR1/Wnt, GCN2-ATF4, epithelial to mesenchymal transition (EMT) and PI3K-AKT., Conclusion: Together, these studies support further investigation of GZD824 as a potential therapeutic agent in endometrial cancer, potentially in combination with immune checkpoint inhibitors., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background: There is evidence that inflammatory arthritis in the form of ankylosing spondylitis (AS), psoriatic arthritis (PsA), and rheumatoid arthritis are both positively and negatively associated with certain female-specific cancers. However, the study results are very heterogeneous., Methods: Based on up to 375,814 European women, we performed an iterative two-sample Mendelian randomization to assess causal effects of the occurrence of the inflammatory arthritis on the risk of female-specific cancer in form of breast, endometrial, and ovarian cancer sites as well as their subtypes. Evidence was strengthened by using similar exposures for plausibility or by replication with a subsequent meta-analysis. P-values were Bonferroni adjusted., Results: Genetic liability to AS was associated with ovarian cancer (OR = 1.03; 95% CI: [1.01; 1.04]; [Formula: see text]=0.029) and liability to PsA with breast cancer (OR = 1.02; CI: [1.01; 1.04]; [Formula: see text]=0.002). Subgroup analyses revealed that the high-grade serous ovarian cancer (OR = 1.04; CI: [1.02; 1.06]; [Formula: see text]=0.015) and the ER- breast cancer (OR = 1.04; CI: [1.01; 1.07]; [Formula: see text]=0.118) appeared to drive the observed associations, respectively. No further associations were found between the remaining inflammatory arthritis phenotypes and female-specific cancers., Conclusions: This study suggests that AS is a risk factor for ovarian cancer, while PsA is linked to an increased breast cancer risk. These results are important for physicians caring women with inflammatory arthritis to advise their patients on cancer screening and preventive measures., (© 2024. The Author(s).)

Background: Inflammation and immune dysregulation are hypothesized contributors to endometrial carcinogenesis; however, the precise underlying mechanisms remain unclear., Methods: We measured pre-diagnostically 152 plasma protein biomarkers in 624 endometrial cancer case-control pairs nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Odds ratios (ORs) were estimated using conditional logistic regression, accounting for confounding and multiple comparisons. Proteins considered as associated with endometrial cancer risk were further tested in a two-sample Mendelian randomization (MR) analysis using summary data from the UK Biobank (n = 52,363) and the Endometrial Cancer Association Consortium (12,270 cases and 46,126 controls)., Findings: In the EPIC nested case-control study, IL-6 [OR per NPX (doubling of concentration) = 1.28 (95% confidence interval (CI) 1.03-1.57)], HGF [1.48 (1.06-2.07)], PIK3AP1 [1.22 (1.00-1.50)] and CLEC4G [1.52 (1.00-2.32)] were positively associated; HSD11B1 [0.67 (0.49-0.91)], SCF [0.68 (0.49-0.94)], and CCL25 [0.80 (0.65-0.99)] were inversely associated with endometrial cancer risk; all estimates had multiple comparisons adjusted P-value > 0.05. In complementary MR analysis, IL-6 [OR per inverse-rank normalized NPX = 1.19 (95% CI 1.04-1.36)] and HSD11B1 [0.91 (0.84-0.99)] were associated with endometrial cancer risk., Interpretation: Altered IL-6 signalling and reduced glucocorticoid activity via HSD11B1 might play important roles in endometrial carcinogenesis., Funding: Funding for IIG&#95;FULL&#95;2021&#95;008 was obtained from Wereld Kanker Onderzoek Fonds (WKOF), as part of the World Cancer Research Fund International grant programme; Funding for INCA&#95;15849 was obtained from Institut National du Cancer (INCa)., Competing Interests: Declaration of interests EJC is the president of the Peaches Womb Cancer Trust and the research advisory committee chair of the Eve Appeal, both roles are voluntary and unpaid. All other authors declare no conflicts of interest., (Copyright © 2024 World Health Organization. Published by Elsevier B.V. All rights reserved.)

Introduced species can negatively impact endemic flora and fauna. Studies have primarily utilized camera trap observations and occupancy modelling to better clarify the presence/absence and temporal overlap of endemic and exotic predators. Longitudinal data from field research sites are important as they can provide a finer understanding of predator dynamics and their effects on endemic species. One such site is the Bezà Mahafaly Special Reserve, in southern Madagascar. Protected since the 1970s, the local human population around Bezà Mahafaly Special Reserve has greatly expanded, leading to habitat disturbance in the surrounding forests and increased contact between local wildlife, people and their livestock and dogs. Here we use a combination of scat sampling, field observations of successful and attempted predations, locations of scat samples with identifiable lemur remains, and camera trap data to better assess the predator ecology at Bezà Mahafaly Special Reserve. Our results indicate that forest cats (Felis catus), are effective predators of both adult and infant lemurs and appear to be a constant mammalian predator, utilizing mammal prey more than dogs. Dogs are both predators and scavengers of lemurs. Civets focus on small prey, such as insects and rodents as well as plant material. The fosa, Cryptoprocta ferox, are also present but may not hunt in the area continuously. The killing of an adult ring-tailed lemur by two men from outside the area indicate culturally imposed taboos against lemur killing may no longer be effective given that new arrivals may not share the same local cultural restrictions. Scat sampling of exotic predators is one way to expand our understanding of exotic and endemic predator impact on lemur populations, and long-term studies with multiple assessments of predation can provide a clearer understanding of how non-endemic and endemic predators affect endangered species survival.

Postdural puncture headache is a frequently encountered complication following procedures such as lumbar puncture, neuraxial anesthesia, or intrathecal drug delivery device implantation. It classically presents as a painful orthostatic headache that is exacerbated when a patient is upright. For treatment, patients are often started on conservative options such as hydration, caffeine, bedrest, and NSAID analgesics; however, certain patients who fail these therapies may require intervention with an epidural blood patch. The epidural blood patch remains the gold standard for treating refractory postdural puncture headache. Contraindications to epidural blood patch include severe coagulopathy, patient refusal, or infection at the intended site of entry. There are no clear consensus recommendations regarding patients with a hematological malignancy and potential risk that autologous blood may seed malignant cells into the neuraxis. In this case report, we present a patient with acute myeloid leukemia who developed a postdural puncture headache after receiving subarachnoid administration of antineoplastics. The patient was refractory to conservative therapy, prompting multidisciplinary consultation and discussion with the patient about the risks and benefits of proceeding with an epidural blood patch. Ultimately, the patient elected to proceed with the offered epidural blood patch which led to complete resolution of his painful headaches and did not cause any spread of malignant cells into his neuraxis or cerebral spinal fluid., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Ross Barman et al.)

Background: Dysregulation of endocrine pathways related to steroid and growth hormones may modify endometrial cancer risk; however, prospective data on testosterone, sex hormone-binding globulin (SHBG) and insulin-like growth factor (IGF)-1 are limited. To elucidate the role of these hormones in endometrial cancer risk we conducted complementary observational and Mendelian randomization (MR) analyses., Methods: The observational analyses included 159,702 women (80% postmenopausal) enrolled in the UK Biobank. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. For MR analyses, genetic variants associated with hormone levels were identified and their association with endometrial cancer (12,906 cases/108,979 controls) was examined using two-sample MR., Results: In the observational analysis, higher circulating concentrations of total (HR per unit inverse normal scale = 1.38, 95% CI = 1.22-1.57) and free testosterone (HR per unit log scale = 2.07, 95% CI = 1.66-2.58) were associated with higher endometrial cancer risk. An inverse association was found for SHBG (HR per unit inverse normal scale = 0.76, 95% CI = 0.67-0.86). Results for testosterone and SHBG were supported by the MR analyses. No association was found between genetically predicted IGF-1 concentration and endometrial cancer risk., Conclusions: Our results support probable causal associations between circulating concentrations of testosterone and SHBG with endometrial cancer risk., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Objectives: Patients with COVID-19 can present to the emergency department (ED) without immediate indication for admission, but with concern for decompensation. Clinical experience has demonstrated that critical illness may present later in the disease course and hypoxia is often the first indication of disease progression. The objectives of this study are to (a) assess feasibility and describe a protocol for ED-based outpatient pulse-oximetry monitoring with structured follow-up and (b) determine rates of ED return, hospitalisation and hypoxia among participants., Methods: Prospective observational study of patients presenting to a single academic ED in Boston with suspected COVID-19. Eligible patients were adults being discharged from the ED with presumed COVID-19. Exclusion criteria included resting oxygen saturation <92%, ambulatory oxygen saturation <90%, heart rate >110 beats per minute or inability to use the device. Study personnel made scripted phone calls on postdischarge days 1, 3 and 7 to review the pulse-oximetry readings and to evaluate for decompensation. Return visit and admission information were collected via medical record and 28-day follow-up calls., Results: 81 patients were enrolled of which 10 (12%) developed hypoxia after their initial discharge from the ED. Overall, 23 (28%) of the 81 patients returned to the ED at least once and 10 of those who returned (43%) were admitted. We successfully contacted 76/81 (94%) of subjects via phone at least once for follow-up assessment., Discussion: Patients are eager and willing to participate in home monitoring systems and are comfortable with using technology, which will allow providers and health systems to extend our hospitals capabilities for tracking patient populations in times of crisis., Conclusions: It is feasible to implement an outpatient pulse-oximetry monitoring protocol to monitor patients discharged from the ED with confirmed or suspected COVID-19., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Previous Mendelian randomization (MR) studies on 25-hydroxyvitamin D (25(OH)D) and cancer have typically adopted a handful of variants and found no relationship between 25(OH)D and cancer; however, issues of horizontal pleiotropy cannot be reliably addressed. Using a larger set of variants associated with 25(OH)D (74 SNPs, up from 6 previously), we perform a unified MR analysis to re-evaluate the relationship between 25(OH)D and ten cancers. Our findings are broadly consistent with previous MR studies indicating no relationship, apart from ovarian cancers (OR 0.89; 95% C.I: 0.82 to 0.96 per 1 SD change in 25(OH)D concentration) and basal cell carcinoma (OR 1.16; 95% C.I.: 1.04 to 1.28). However, after adjustment for pigmentation related variables in a multivariable MR framework, the BCC findings were attenuated. Here we report that lower 25(OH)D is unlikely to be a causal risk factor for most cancers, with our study providing more precise confidence intervals than previously possible.

Importance: Data on the efficacy of hydroxychloroquine for the treatment of coronavirus disease 2019 (COVID-19) are needed., Objective: To determine whether hydroxychloroquine is an efficacious treatment for adults hospitalized with COVID-19., Design, Setting, and Participants: This was a multicenter, blinded, placebo-controlled randomized trial conducted at 34 hospitals in the US. Adults hospitalized with respiratory symptoms from severe acute respiratory syndrome coronavirus 2 infection were enrolled between April 2 and June 19, 2020, with the last outcome assessment on July 17, 2020. The planned sample size was 510 patients, with interim analyses planned after every 102 patients were enrolled. The trial was stopped at the fourth interim analysis for futility with a sample size of 479 patients., Interventions: Patients were randomly assigned to hydroxychloroquine (400 mg twice daily for 2 doses, then 200 mg twice daily for 8 doses) (n = 242) or placebo (n = 237)., Main Outcomes and Measures: The primary outcome was clinical status 14 days after randomization as assessed with a 7-category ordinal scale ranging from 1 (death) to 7 (discharged from the hospital and able to perform normal activities). The primary outcome was analyzed with a multivariable proportional odds model, with an adjusted odds ratio (aOR) greater than 1.0 indicating more favorable outcomes with hydroxychloroquine than placebo. The trial included 12 secondary outcomes, including 28-day mortality., Results: Among 479 patients who were randomized (median age, 57 years; 44.3% female; 37.2% Hispanic/Latinx; 23.4% Black; 20.1% in the intensive care unit; 46.8% receiving supplemental oxygen without positive pressure; 11.5% receiving noninvasive ventilation or nasal high-flow oxygen; and 6.7% receiving invasive mechanical ventilation or extracorporeal membrane oxygenation), 433 (90.4%) completed the primary outcome assessment at 14 days and the remainder had clinical status imputed. The median duration of symptoms prior to randomization was 5 days (interquartile range [IQR], 3 to 7 days). Clinical status on the ordinal outcome scale at 14 days did not significantly differ between the hydroxychloroquine and placebo groups (median [IQR] score, 6 [4-7] vs 6 [4-7]; aOR, 1.02 [95% CI, 0.73 to 1.42]). None of the 12 secondary outcomes were significantly different between groups. At 28 days after randomization, 25 of 241 patients (10.4%) in the hydroxychloroquine group and 25 of 236 (10.6%) in the placebo group had died (absolute difference, -0.2% [95% CI, -5.7% to 5.3%]; aOR, 1.07 [95% CI, 0.54 to 2.09])., Conclusions and Relevance: Among adults hospitalized with respiratory illness from COVID-19, treatment with hydroxychloroquine, compared with placebo, did not significantly improve clinical status at day 14. These findings do not support the use of hydroxychloroquine for treatment of COVID-19 among hospitalized adults., Trial Registration: ClinicalTrials.gov: NCT04332991.

Background: Insulinemia and type 2 diabetes (T2D) have been associated with endometrial cancer risk in numerous observational studies. However, the causality of these associations is uncertain. Here we use a Mendelian randomization (MR) approach to assess whether insulinemia and T2D are causally associated with endometrial cancer., Methods: We used single nucleotide polymorphisms (SNPs) associated with T2D (49 variants), fasting glucose (36 variants), fasting insulin (18 variants), early insulin secretion (17 variants), and body mass index (BMI) (32 variants) as instrumental variables in MR analyses. We calculated MR estimates for each risk factor with endometrial cancer using an inverse-variance weighted method with SNP-endometrial cancer associations from 1287 case patients and 8273 control participants., Results: Genetically predicted higher fasting insulin levels were associated with greater risk of endometrial cancer (odds ratio [OR] per standard deviation = 2.34, 95% confidence internal [CI] = 1.06 to 5.14, P = .03). Consistently, genetically predicted higher 30-minute postchallenge insulin levels were also associated with endometrial cancer risk (OR = 1.40, 95% CI = 1.12 to 1.76, P = .003). We observed no associations between genetic risk of type 2 diabetes (OR = 0.91, 95% CI = 0.79 to 1.04, P = .16) or higher fasting glucose (OR = 1.00, 95% CI = 0.67 to 1.50, P = .99) and endometrial cancer. In contrast, endometrial cancer risk was higher in individuals with genetically predicted higher BMI (OR = 3.86, 95% CI = 2.24 to 6.64, P = 1.2x10(-6))., Conclusion: This study provides evidence to support a causal association of higher insulin levels, independently of BMI, with endometrial cancer risk., (© The Author 2015. Published by Oxford University Press.)

A patient with a mucinous appendiceal cancer presents to the surgeon complaining of abdominal discomfort and nausea. Having undergone a prior right hemicolectomy, the patient has been disease free and on surveillance with clinical and carcinogenic antigen (CEA) monitoring. The CEA was noted to be elevated and a computed tomography scan revealed peritoneal nodules throughout the abdomen with a presumptive diagnosis of pseudomyxoma peritonei (progressive peritoneal implants from a mucinous primary). Several therapeutic options were offered and the patient selected to undergo cytoreductive surgery (CRS) with the potential to receive hyperthermic interoperative chemotherapy (HIPEC). Extensive resection was performed, including removal of the entire greater omentum, partial gastrectomy, and total pelvic exenteration with end colostomy and ileal conduit. Reassessment of the peritoneal cavity after the resections revealed almost complete cytoreduction. HIPEC was performed with mitomycin C and, after drainage and abdominal washing, the intestinal segments were anastomosed and the abdominal wall closed. Seven days postoperatively, an acute abdomen with septic shock developed as a result of a leak from the ileocolonic anastomosis. The patient returned to the operating room and an exploratory laparotomy, a small bowel resection, a resection of the ileocolonic anastomosis, and an abdominal washout were performed. Edema of the bowel caused by peritonitis resulting from the anastomotic leak necessitated delayed closure of the abdominal wall. A temporary abdominal closure using the ABThera™ Open Abdomen Negative Pressure Therapy system was applied and the abdomen was eventually closed.

The human tissue Kallikrein family consists of 15 genes with the majority shown to be differentially expressed in cancers and/or indicators of cancer prognosis. We sought to elucidate the role of common genetic variation in four of the Kallikrein genes, KLK5, KLK6, KLK12, and KLK13, in prostate cancer risk and tumor aggressiveness. Genotyping of all 22 tagging single nucleotide polymorphisms (tagSNPs) in the KLK5, KLK6, KLK12, and KLK13 genes was performed in approximately 1,000 prostate cancer cases and 1,300 male controls from Australia. Data from any positive results were also accessed for 1,844 cases and 1,886 controls from a previously published prostate cancer genome-wide association study set from the United Kingdom. For one SNP in KLK12, rs3865443, there was evidence for association with prostate cancer risk of similar direction and magnitude in the replication set to that seen in the Australian cohort. We conducted genotyping of a further 309 prostate cancer cases, and combined analyses revealed an increased risk of prostate cancer for carriers of the rare homozygous genotype for rs3865443 (OR 1.28, 95% CI 1.04-1.57; P = 0.018). No other tagSNPs in the KLK5, KLK6, and KLK13 genes were consistently associated with prostate cancer risk or tumor aggressiveness. Analysis of a combined sample of 3,153 cases and 3,199 controls revealed the KLK12 tagSNP rs3865443 to be marginally statistically significantly associated with risk of prostate cancer. Considering the total number of SNPs investigated in this study, this finding should be interpreted cautiously and requires additional validation from very large datasets such as those of the Prostate Cancer Association group to investigate cancer associated alterations (PRACTICAL) Consortium., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Experimental and epidemiologic evidence have suggested that chronic inflammation may play a critical role in endometrial carcinogenesis., Methods: To investigate this hypothesis, a two-stage study was carried out to evaluate single-nucleotide polymorphisms (SNP) in inflammatory pathway genes in association with endometrial cancer risk. In stage I, 64 candidate pathway genes were identified and 4,542 directly genotyped or imputed SNPs were analyzed among 832 endometrial cancer cases and 2,049 controls, using data from the Shanghai Endometrial Cancer Genetics Study. Linkage disequilibrium of stage I SNPs significantly associated with endometrial cancer (P < 0.05) indicated that the majority of associations could be linked to one of 24 distinct loci. One SNP from each of the 24 loci was then selected for follow-up genotyping. Of these, 21 SNPs were successfully designed and genotyped in stage II, which consisted of 10 additional studies including 6,604 endometrial cancer cases and 8,511 controls., Results: Five of the 21 SNPs had significant allelic odds ratios (ORs) and 95% confidence intervals (CI) as follows: FABP1, 0.92 (0.85-0.99); CXCL3, 1.16 (1.05-1.29); IL6, 1.08 (1.00-1.17); MSR1, 0.90 (0.82-0.98); and MMP9, 0.91 (0.87-0.97). Two of these polymorphisms were independently significant in the replication sample (rs352038 in CXCL3 and rs3918249 in MMP9). The association for the MMP9 polymorphism remained significant after Bonferroni correction and showed a significant association with endometrial cancer in both Asian- and European-ancestry samples., Conclusions: These findings lend support to the hypothesis that genetic polymorphisms in genes involved in the inflammatory pathway may contribute to genetic susceptibility to endometrial cancer. Impact statement: This study adds to the growing evidence that inflammation plays an important role in endometrial carcinogenesis.

The Kallikrein ( KLK ) gene locus encodes a family of serine proteases and is the largest contiguous cluster of protease-encoding genes attributed an evolutionary age of 330 million years. The KLK locus has been implicated asa high susceptibility risk loci in numerous cancer studies through the last decade. The KLK3 gene already has established clinical relevance as a biomarker in prostate cancer prognosis through its encoded protein, prostate-specific antigen. Data mined through genome-wide association studies (GWAS) and next-generation sequencing point to many important candidate single nucleotide polymorphisms(SNPs) in KLK3 and other KLK genes. SNPs in the KLK locus have been found to be associated with several diseases including cancer, hypertension, cardiovascular disease and atopic dermatitis. Moreover, introducing a model incorporating SNPs to improve the efficiency of prostate-specific antigen in detecting malignant states of prostate cancer has been recently suggested. Establishing the functional relevance of these newly-discovered SNPs, and their interactions with each other, through in silico investigations followed by experimental validation,can accelerate the discovery of diagnostic and prognostic biomarkers. In this review, we discuss the various genetic association studies on the KLK loci identified either through candidate gene association studies or at the GWAS and post-GWAS front to aid researchers in streamlining their search for the most significant, relevant and therapeutically promising candidate KLK gene and/or SNP for future investigations.

Background: Genome-wide association studies (GWAS) have identified more than 100 genetic loci for various cancers. However, only one is for endometrial cancer., Methods: We conducted a three-stage GWAS including 8,492 endometrial cancer cases and 16,596 controls. After analyzing 585,963 single-nucleotide polymorphisms (SNP) in 832 cases and 2,682 controls (stage I) from the Shanghai Endometrial Cancer Genetics Study, we selected the top 106 SNPs for in silico replication among 1,265 cases and 5,190 controls from the Australian/British Endometrial Cancer GWAS (stage II). Nine SNPs showed results consistent in direction with stage I with P < 0.1. These nine SNPs were investigated among 459 cases and 558 controls (stage IIIa) and six SNPs showed a direction of association consistent with stages I and II. These six SNPs, plus two additional SNPs selected on the basis of linkage disequilibrium and P values in stage II, were investigated among 5,936 cases and 8,166 controls from an additional 11 studies (stage IIIb)., Results: SNP rs1202524, near the CAPN9 gene on chromosome 1q42.2, showed a consistent association with endometrial cancer risk across all three stages, with ORs of 1.09 [95% confidence interval (CI), 1.03-1.16] for the A/G genotype and 1.17 (95% CI, 1.05-1.30) for the G/G genotype (P = 1.6 × 10(-4) in combined analyses of all samples). The association was stronger when limited to the endometrioid subtype, with ORs (95% CI) of 1.11 (1.04-1.18) and 1.21 (1.08-1.35), respectively (P = 2.4 × 10(-5))., Conclusions: Chromosome 1q42.2 may host an endometrial cancer susceptibility locus., Impact: This study identified a potential genetic locus for endometrial cancer risk.

Kallikrein 14 (KLK14) has been proposed as a useful prognostic marker in prostate cancer, with expression reported to be associated with tumour characteristics such as higher stage and Gleason score. KLK14 tumour expression has also shown the potential to predict prostate cancer patients at risk of disease recurrence after radical prostatectomy. The KLKs are a remarkably hormone-responsive family of genes, although detailed studies of androgen regulation of KLK14 in prostate cancer have not been undertaken to date. Using in vitro studies, we have demonstrated that unlike many other prostatic KLK genes that are strictly androgen responsive, KLK14 is more broadly expressed and inversely androgen regulated in prostate cancer cells. Given these results and evidence that KLK14 may play a role in prostate cancer prognosis, we also investigated whether common genetic variants in the KLK14 locus are associated with risk and/or aggressiveness of prostate cancer in approximately 1200 prostate cancer cases and 1300 male controls. Of 41 single nucleotide polymorphisms assessed, three were associated with higher Gleason score (≥7): rs17728459 and rs4802765, both located upstream of KLK14, and rs35287116, which encodes a p.Gln33Arg substitution in the KLK14 signal peptide region. Our findings provide further support for KLK14 as a marker of prognosis in prostate cancer.

The Kallikrein-related peptidase, KLK4, has been shown to be significantly overexpressed in prostate tumours in numerous studies and is suggested to be a potential biomarker for prostate cancer. KLK4 may also play a role in prostate cancer progression through its involvement in epithelial-mesenchymal transition, a more aggressive phenotype, and metastases to bone. It is well known that genetic variation has the potential to affect gene expression and/or various protein characteristics and hence we sought to investigate the possible role of single nucleotide polymorphisms (SNPs) in the KLK4 gene in prostate cancer. Assessment of 61 SNPs in the KLK4 locus (± 10 kb) in approximately 1300 prostate cancer cases and 1300 male controls for associations with prostate cancer risk and/or prostate tumour aggressiveness (Gleason score <7 versus ≥ 7) revealed 7 SNPs to be associated with a decreased risk of prostate cancer at the P(trend)<0.05 significance level. Three of these SNPs, rs268923, rs56112930 and the HapMap tagSNP rs7248321, are located several kb upstream of KLK4; rs1654551 encodes a non-synonymous serine to alanine substitution at position 22 of the long isoform of the KLK4 protein, and the remaining 3 risk-associated SNPs, rs1701927, rs1090649 and rs806019, are located downstream of KLK4 and are in high linkage disequilibrium with each other (r(2) ≥ 0.98). Our findings provide suggestive evidence of a role for genetic variation in the KLK4 locus in prostate cancer predisposition.

Endometrial cancer is the most common malignancy of the female genital tract in developed countries. To identify genetic variants associated with endometrial cancer risk, we performed a genome-wide association study involving 1,265 individuals with endometrial cancer (cases) from Australia and the UK and 5,190 controls from the Wellcome Trust Case Control Consortium. We compared genotype frequencies in cases and controls for 519,655 SNPs. Forty seven SNPs that showed evidence of association with endometrial cancer in stage 1 were genotyped in 3,957 additional cases and 6,886 controls. We identified an endometrial cancer susceptibility locus close to HNF1B at 17q12 (rs4430796, P = 7.1 × 10(-10)) that is also associated with risk of prostate cancer and is inversely associated with risk of type 2 diabetes.

Background: KLK15 over-expression is reported to be a significant predictor of reduced progression-free survival and overall survival in ovarian cancer. Our aim was to analyse the KLK15 gene for putative functional single nucleotide polymorphisms (SNPs) and assess the association of these and KLK15 HapMap tag SNPs with ovarian cancer survival., Results: In silico analysis was performed to identify KLK15 regulatory elements and to classify potentially functional SNPs in these regions. After SNP validation and identification by DNA sequencing of ovarian cancer cell lines and aggressive ovarian cancer patients, 9 SNPs were shortlisted and genotyped using the Sequenom iPLEX Mass Array platform in a cohort of Australian ovarian cancer patients (N = 319). In the Australian dataset we observed significantly worse survival for the KLK15 rs266851 SNP in a dominant model (Hazard Ratio (HR) 1.42, 95% CI 1.02-1.96). This association was observed in the same direction in two independent datasets, with a combined HR for the three studies of 1.16 (1.00-1.34). This SNP lies 15 bp downstream of a novel exon and is predicted to be involved in mRNA splicing. The mutant allele is also predicted to abrogate an HSF-2 binding site., Conclusions: We provide evidence of association for the SNP rs266851 with ovarian cancer survival. Our results provide the impetus for downstream functional assays and additional independent validation studies to assess the role of KLK15 regulatory SNPs and KLK15 isoforms with alternative intracellular functional roles in ovarian cancer survival.

Overweight and obesity are strongly associated with endometrial cancer. Several independent genome-wide association studies recently identified two common polymorphisms, FTO rs9939609 and MC4R rs17782313, that are linked to increased body weight and obesity. We examined the association of FTO rs9939609 and MC4R rs17782313 with endometrial cancer risk in a pooled analysis of nine case-control studies within the Epidemiology of Endometrial Cancer Consortium (E2C2). This analysis included 3601 non-Hispanic white women with histologically-confirmed endometrial carcinoma and 5275 frequency-matched controls. Unconditional logistic regression models were used to assess the relation of FTO rs9939609 and MC4R rs17782313 genotypes to the risk of endometrial cancer. Among control women, both the FTO rs9939609 A and MC4R rs17782313 C alleles were associated with a 16% increased risk of being overweight (p = 0.001 and p = 0.004, respectively). In case-control analyses, carriers of the FTO rs9939609 AA genotype were at increased risk of endometrial carcinoma compared to women with the TT genotype [odds ratio (OR)  = 1.17; 95% confidence interval (CI): 1.03-1.32, p = 0.01]. However, this association was no longer apparent after adjusting for body mass index (BMI), suggesting mediation of the gene-disease effect through body weight. The MC4R rs17782313 polymorphism was not related to endometrial cancer risk (per allele OR = 0.98; 95% CI: 0.91-1.06; p = 0.68). FTO rs9939609 is a susceptibility marker for white non-Hispanic women at higher risk of endometrial cancer. Although FTO rs9939609 alone might have limited clinical or public health significance for identifying women at high risk for endometrial cancer beyond that of excess body weight, further investigation of obesity-related genetic markers might help to identify the pathways that influence endometrial carcinogenesis.

Background: Kallikrein 15 (KLK15)/Prostinogen is a plausible candidate for prostate cancer susceptibility. Elevated KLK15 expression has been reported in prostate cancer and it has been described as an unfavorable prognostic marker for the disease., Objectives: We performed a comprehensive analysis of association of variants in the KLK15 gene with prostate cancer risk and aggressiveness by genotyping tagSNPs, as well as putative functional SNPs identified by extensive bioinformatics analysis. METHODS AND DATA SOURCES: Twelve out of 22 SNPs, selected on the basis of linkage disequilibrium pattern, were analyzed in an Australian sample of 1,011 histologically verified prostate cancer cases and 1,405 ethnically matched controls. Replication was sought from two existing genome wide association studies (GWAS): the Cancer Genetic Markers of Susceptibility (CGEMS) project and a UK GWAS study., Results: Two KLK15 SNPs, rs2659053 and rs3745522, showed evidence of association (p<0.05) but were not present on the GWAS platforms. KLK15 SNP rs2659056 was found to be associated with prostate cancer aggressiveness and showed evidence of association in a replication cohort of 5,051 patients from the UK, Australia, and the CGEMS dataset of US samples. A highly significant association with Gleason score was observed when the data was combined from these three studies with an Odds Ratio (OR) of 0.85 (95% CI = 0.77-0.93; p = 2.7×10(-4)). The rs2659056 SNP is predicted to alter binding of the RORalpha transcription factor, which has a role in the control of cell growth and differentiation and has been suggested to control the metastatic behavior of prostate cancer cells., Conclusions: Our findings suggest a role for KLK15 genetic variation in the etiology of prostate cancer among men of European ancestry, although further studies in very large sample sets are necessary to confirm effect sizes.

Objectives: We sought to evaluate the effect of polymorphisms in the VEGF (Vascular Endothelial Growth Factor) gene on overall survival in ovarian cancer patients., Methods: A sample of 319 women diagnosed with primary invasive epithelial ovarian cancer in Australia between 1985 and 1997, recruited as incident cases, were genotyped for four VEGF single nucleotide polymorphisms (three tagSNPs and one functional SNP) using the Sequenom MassARRAY platform. A SNP found to be associated with ovarian cancer survival in this sample set was then evaluated in two independent datasets in an attempt to replicate the association., Results: VEGF tagSNPs rs3025033 and rs2146323 were not associated with ovarian cancer survival in the Australian sample. Ovarian cancer patients homozygous for tagSNP rs833068 or the functional SNP rs2010963 displayed significantly shortened overall survival in the Australian sample (HR 2.09, 95% CI 1.16-3.78), an effect most apparent in the first 5years after diagnosis. This association was not replicated in two independent datasets., Conclusions: Findings from this study provide no evidence that rs3025033 and rs2146323 VEGF polymorphisms are associated with ovarian cancer survival. Although homozygous carriers of the tagSNP rs833068 experienced significantly worse survival in our Australian dataset, we were unable to replicate this in two independent datasets., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Introduction: Obesity and diabetes are known risk factors for endometrial cancer; thus, the genetic risk factors of these phenotypes might also be associated with endometrial cancer risk. To evaluate this hypothesis, we genotyped tag-single nucleotide polymorphisms (SNP) and candidate SNPs in FTO and HHEX in a primary set of 417 endometrial cancer cases and 406 population-based controls, and validated significant findings in a replication set of approximately 2,347 cases and 3,140 controls from three additional studies., Methods: We genotyped 189 tagSNPs in FTO (including rs8050136) and five tagSNPs in HHEX (including rs1111875) in the primary set and one SNP each in FTO (rs12927155) and HHEX (rs1111875) in the validation set. Per allele odds ratios (OR) and 95% confidence intervals (CI) were calculated to estimate the association between the genotypes of each SNPs (as an ordinal variable) and endometrial cancer risk using unconditional logistic regression models, controlling for age and site., Results: In the primary study, the most significant finding in FTO was rs12927155 (OR, 1.56; 95% CI, 1.21-2.01; P = 5.8 x 10(-4)), and in HHEX, it was rs1111875 (OR, 0.80; 95% CI, 0.66-0.97; P = 0.026). In the validation studies, the pooled per allele OR, adjusted for age and study for FTO, was rs12927155 (OR, 0.94; 95% CI, 0.83-1.06; P = 0.29), whereas for HHEX, it was rs1111875 (OR, 1.00; 95% CI, 0.92-1.10; P = 0.96)., Conclusion: Our data indicate that common genetic variants in two genes previously related to obesity (FTO) and diabetes (HHEX) by genome-wide association scans were not associated with endometrial cancer risk., Impact: Polymorphisms in FTO and HHEX are unlikely to have large effects on endometrial cancer risk but may have weaker effects., ((c)2010 AACR.)

Introduction: Kallikrein-related peptidase 10 (KLK10) overexpression is a predictor of poor disease outcome in women with late-stage ovarian cancer. We aimed to identify whether KLK10 overexpression could be attributed to genetic variants, in particular, in hormone response elements or transcription factor binding sites., Methods: Cox regression analysis was used to assess the association between 2 tag and 1 exonic KLK10 single nucleotide polymorphisms (SNPs) and the survival of 319 patients with ovarian cancer. Four different ovarian cancer cell lines were investigated for KLK10 expression after hormone stimulation, and sequence variation in the 3.6-Kb upstream of the KLK10 start site. In silico analyses of SNPs in cell lines and from published databases were undertaken to identify further research novel and potentially functional SNPs that are not covered by tag SNPs., Results: The KLK10 SNPs investigated were not associated with ovarian cancer survival. However, steroid hormone treatment of ovarian cell lines showed KLK10 up-regulation in response to estrogen and estrogen plus progesterone treatments in the aggressive cell line PEO1 and affirmed a role for KLK10 in aggressive ovarian cancer. Potentially functional KLK10 SNPs were identified by cell line sequencing and bioinformatic analysis., Conclusion: Potentially functional candidate KLK10 SNPs require investigation in future association studies of ovarian cancer risk and survival, including rs3760738 identified in aggressive ovarian cancer cell lines and predicted to affect transcription factor binding sites.

A recent genome-wide association study found that genetic variants on chromosomes 3, 6, 7, 10, 11, 19 and X were associated with prostate cancer risk. We evaluated the most significant single-nucleotide polymorphisms (SNP) in these loci using a worldwide consortium of 13 groups (PRACTICAL). Blood DNA from 7,370 prostate cancer cases and 5,742 male controls was analyzed by genotyping assays. Odds ratios (OR) associated with each genotype were estimated using unconditional logistic regression. Six of the seven SNPs showed clear evidence of association with prostate cancer (P = 0.0007-P = 10(-17)). For each of these six SNPs, the estimated per-allele OR was similar to those previously reported and ranged from 1.12 to 1.29. One SNP on 3p12 (rs2660753) showed a weaker association than previously reported [per-allele OR, 1.08 (95% confidence interval, 1.00-1.16; P = 0.06) versus 1.18 (95% confidence interval, 1.06-1.31)]. The combined risks associated with each pair of SNPs were consistent with a multiplicative risk model. Under this model, and in combination with previously reported SNPs on 8q and 17q, these loci explain 16% of the familial risk of the disease, and men in the top 10% of the risk distribution have a 2.1-fold increased risk relative to general population rates. This study provides strong confirmation of these susceptibility loci in multiple populations and shows that they make an important contribution to prostate cancer risk prediction.

CD44 glycoproteins are present on the surfaces of many hematopoietic cells and in some cases can bind hyaluronan, a major component of the extracellular matrix. In the present study, we have found that newly explanted human peripheral blood monocytes (PBMs) exhibit a major CD44 band of 85 kDa, whereas autologous alveolar macrophages (AM phi) express multiple isoforms ranging from 85 to 200 kDa. Within 4 h in culture, PBMs began expressing new CD44 isoforms of 120, 150, and 180 kDa. Newly explanted AM phi specifically bound [3H]hyaluronan (135 cpm/microgram protein), but newly explanted PBMs did not. However, in vitro cultured PBM progressively acquired the ability to bind [3H]hyaluronan and exhibited specific binding of hyaluronan similar to that of AM phi (113 cpm/microgram protein) after 4 days in culture. In both case, the binding of [3H]hyaluronan was specifically inhibited by the addition of monoclonal antibody directed against CD44. AM phi readily degraded [3H]hyaluronan and reached a plateau after 4 days in culture (115 cpm/microgram protein). Newly explanted PBM exhibit no hyaluronan degradation and only a small degradative activity after 4 days in culture (6 to 11 cpm/microgram protein). Thus, CD44 expression and function appear to change as PBM mature in vitro resembling more that found in AM phi.

Since first described in 1984, nontraumatic pneumothoraces in patients with AIDS has become more common. When compared with spontaneous pneumothorax in the general population, pneumothoraces in patients with AIDS are often complicated by prolonged air leaks as well as higher recurrence rates. Chemical pleurodesis has an important role in the management of these complications. The most experience with chemical pleurodesis uses tetracycline hydrochloride as the sclerosing agent; however, this agent is no longer available. Doxycycline has been used in pleurodesis of malignant effusions, but its use in managing pneumothoraces is limited. We present five patients who have AIDS with a total of seven pneumothoraces. Each patient experienced a persistent air leak. Six of the pneumothoraces were managed successfully with doxycycline. Although the follow-up period was limited, there were no recurrences noted and the only side effect seen was chest pain in four which was easily controlled with narcotics. Doxycycline sclerotherapy can be used effectively for pleurodesis in the management of nontraumatic pneumothorax in the patient with AIDS.

Passive Heymann nephritis (PHN) is an animal model of immune-complex-induced renal disease resembling human membranous glomerulonephritis. It was induced in rats by injecting rabbit antiserum directed against glycoprotein antigens isolated from rat embryonic visceral yolk-sac microvilli (VYS-MV). The glycoprotein antigens were isolated by extracting the VYS-MV with detergent Nonidet P-40 followed by gel filtration in Sephacryl S-300 and finally by lectin affinity chromatography with Ricinus communis agglutinin I. In vitro immunofluorescent localization studies demonstrated that the nephritogenic antibodies were localized along the apical region of the visceral yolk-sac endodermal cells and the brush border of the proximal tubular cells of the kidney. Rats injected with a single dose of the antiserum manifested proteinuria. Indirect immunofluorescent studies showed that the injected rabbit IgG was localized in vivo along the capillary walls of the glomerulus in a granular fashion. Electron microscopic examination of the same kidney glomeruli revealed numerous electron-dense deposits along the lamina rara externa of the glomerular basement membrane. Fusion of the epithelial foot processes was also present. These findings represent the typical immunopathological characteristics of Heymann nephritis. Furthermore, with the aid of Ouchterlony analysis, the antiserum against the isolated VYS antigens exhibited an immunoprecipitin band which was in common with that formed by the antiserum against the homogeneous nephritogenic antigen (gp330) of renal brush border origin. Thus, the nephritogenic antigens which have been found to be associated with the brush border of the renal proximal tubules may also be present or cross-reacted in the microvilli of the rat embryonic visceral yolk-sac.