Convergence of coronary artery disease genes onto endothelial cell programs.

Linking variants from genome-wide association studies (GWAS) to underlying mechanisms of disease remains a challenge1-3. For some diseases, a successful strategy has been to look for cases in which multiple GWAS loci contain genes that act in the same biological pathway1-6. However, our knowledge of which genes act in which pathways is incomplete, particularly for cell-type-specific pathways or understudied genes. Here we introduce a method to connect GWAS variants to functions. This method links variants to genes using epigenomics data, links genes to pathways de novo using Perturb-seq and integrates these data to identify convergence of GWAS loci onto pathways. We apply this approach to study the role of endothelial cells in genetic risk for coronary artery disease (CAD), and discover 43 CAD GWAS signals that converge on the cerebral cavernous malformation (CCM) signalling pathway. Two regulators of this pathway, CCM2 and TLNRD1, are each linked to a CAD risk variant, regulate other CAD risk genes and affect atheroprotective processes in endothelial cells. These results suggest a model whereby CAD risk is driven in part by the convergence of causal genes onto a particular transcriptional pathway in endothelial cells. They highlight shared genes between common and rare vascular diseases (CAD and CCM), and identify TLNRD1 as a new, previously uncharacterized member of the CCM signalling pathway. This approach will be widely useful for linking variants to functions for other common polygenic diseases.

Concepts and prospects of minimally invasive colorectal cancer surgery.

It is important that clinical radiologists understand and appreciate the minimally invasive surgery (MIS) options available to surgeons. Operative technologies are constantly evolving, and accurate, informed interpretation of clinical imaging is essential for optimum surgical management. Concurrent advancements in both MIS and radiological staging have certainly improved treatment decisions and outcomes. This article outlines the history, current concepts, evolving techniques, and future prospects of MIS as it pertains to colorectal cancer surgery.

Is it time for one-step nucleic acid amplification (OSNA) in colorectal cancer? A systematic review and meta-analysis.

BACKGROUND: Lymph node metastasis (LNM) is prognostic in colorectal cancer (CRC). However, evaluation by routine haematoxylin and eosin histology (HE) limits nodal examination and is subjective. Missed LNMs from tissue allocation bias (TAB) might under-stage disease, leading to under-treatment. One-step nucleic acid amplification (OSNA) for CK19 messenger ribonucleic acid (mRNA), a marker of LNM, analyses the whole node. The aim of the present systematic review and meta-analysis was to assess recent studies on OSNA versus HE and its implications for CRC staging and treatment. METHODS: Databases including OVID, Medline and Google Scholar were searched for OSNA, LNM and CRC. Study results were pooled using a random-effects model. Summary receiver operator curves (SROC) assessed OSNA's performance in detecting LNM when compared to routine HE histology. RESULTS: Five case-control studies analysing 4080 nodes from 622 patients were included. The summary estimates of pooled results for OSNA were sensitivity 0.90 [95% confidence interval (CI) 0.86-0.93], specificity 0.94 (95% CI 0.93-0.95) and diagnostic odds ratio 179.5 (CI 58.35-552.2, p < 0.0001). The SROC curve indicated a maximum joint sensitivity and specificity of 0.88 and area under the curve of 0.94, p < 0.0001. On average, 5.4% HE-negative nodes were upstaged by OSNA. CONCLUSIONS: OSNA is as good as routine HE. It may avoid TAB and offer a more objective and standardised assay of LNM. However, for upstaging, its usefulness as an adjunct to HE or superiority to HE requires further assessment of the benefits, if any, of adjuvant therapy in patients upstaged by OSNA.

Targeting mTOR and survivin concurrently potentiates radiation therapy in renal cell carcinoma by suppressing DNA damage repair and amplifying mitotic catastrophe.

BACKGROUND: Renal cell carcinoma (RCC) was historically considered to be less responsive to radiation therapy (RT) compared to other cancer indications. However, advancements in precision high-dose radiation delivery through single-fraction and multi-fraction stereotactic ablative radiotherapy (SABR) have led to better outcomes and reduced treatment-related toxicities, sparking renewed interest in using RT to treat RCC. Moreover, numerous studies have revealed that certain therapeutic agents including chemotherapies can increase the sensitivity of tumors to RT, leading to a growing interest in combining these treatments. Here, we developed a rational combination of two radiosensitizers in a tumor-targeted liposomal formulation for augmenting RT in RCC. The objective of this study is to assess the efficacy of a tumor-targeted liposomal formulation combining the mTOR inhibitor everolimus (E) with the survivin inhibitor YM155 (Y) in enhancing the sensitivity of RCC tumors to radiation. EXPERIMENTAL DESIGN: We slightly modified our previously published tumor-targeted liposomal formulation to develop a rational combination of E and Y in a single liposomal formulation (EY-L) and assessed its efficacy in RCC cell lines in vitro and in RCC tumors in vivo. We further investigated how well EY-L sensitizes RCC cell lines and tumors toward radiation and explored the underlying mechanism of radiosensitization. RESULTS: EY-L outperformed the corresponding single drug-loaded formulations E-L and Y-L in terms of containing primary tumor growth and improving survival in an immunocompetent syngeneic mouse model of RCC. EY-L also exhibited significantly higher sensitization of RCC cells towards radiation in vitro than E-L and Y-L. Additionally, EY-L sensitized RCC tumors towards radiation therapy in xenograft and murine RCC models. EY-L mediated induction of mitotic catastrophe via downregulation of multiple cell cycle checkpoints and DNA damage repair pathways could be responsible for the augmentation of radiation therapy. CONCLUSION: Taken together, our study demonstrated the efficacy of a strategic combination therapy in sensitizing RCC to radiation therapy via inhibition of DNA damage repair and a substantial increase in mitotic catastrophe. This combination therapy may find its use in the augmentation of radiation therapy during the treatment of RCC patients.

The benefits of index telephone consultations in patients referred on the two-week wait colorectal cancer pathway.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic led to hospitals in the UK substituting face-to-face (FtF) clinics with virtual clinic (VC) appointments. We evaluated the use of virtual two-week wait (2-ww) lower gastrointestinal (LGI) clinic appointments, conducted using telephone calls at a district general hospital in England. METHODS: Patients undergoing index outpatient 2-ww LGI clinic assessment between 1 June 2019 and 31 October 2019 (FtF group) and 1 June 2020 and 31 October 2020 (VC group) were identified. Relevant data were obtained using electronic patient records. Compliance with national cancer waiting time targets was assessed. Environmental and financial impact analyses were performed. RESULTS: In total, 1,531 patients were analysed (median age=70, male=852, 55.6%). Of these, 757 (49.4%) were assessed virtually via telephone; the remainder were seen FtF (n=774, 50.6%). Ninety-two (6%, VC=44, FtF=48) patients had malignant pathology and 64 (4.2%) had colorectal cancer (CRC); of these, 46 (71.9%, VC=26, FtF=20) underwent treatment with curative intent. The median waiting times to index appointment, investigation and diagnosis were significantly lower following VC assessment (p<0.001). The cancer detection rates (p=0.749), treatments received (p=0.785) and median time to index treatment for CRC patients (p=0.156) were similar. A significantly higher proportion of patients were seen within two weeks of referral in the VC group (p<0.001). VC appointments saved patients a total of 9,288 miles, 0.7 metric tonnes of CO2 emissions and £7,482.97. Taxpayers saved £80,242.00 from VCs. No formal complaints were received from patients or staff in the VC group. CONCLUSION: Virtual 2-ww LGI clinics were effective, safe and were associated with tangible environmental and financial benefits.

Targeting mTOR and Survivin Concurrently Potentiates Radiation Therapy in Renal Cell Carcinoma by Suppressing DNA Damage Repair and Amplifying Mitotic Catastrophe.

Background: Renal cell carcinoma (RCC) was historically considered to be less responsive to radiation therapy (RT) compared to other cancer indications. However, advancements in precision high-dose radiation delivery through single-fraction and multi-fraction stereotactic ablative radiotherapy (SABR) have led to better outcomes and reduced treatment-related toxicities, sparking renewed interest in using RT to treat RCC. Moreover, numerous studies have revealed that certain therapeutic agents including chemotherapies can increase the sensitivity of tumors to RT, leading to a growing interest in combining these treatments. Here, we developed a rational combination of two radiosensitizers in a tumor-targeted liposomal formulation for augmenting RT in RCC. The objective of this study is to assess the efficacy of a tumor-targeted liposomal formulation combining the mTOR inhibitor everolimus (E) with the survivin inhibitor YM155 (Y) in enhancing the sensitivity of RCC tumors to radiation. Experimental Design: We slightly modified our previously published tumor-targeted liposomal formulation to develop a rational combination of E and Y in a single liposomal formulation (EY-L) and assessed its efficacy in RCC cell lines in vitro and in RCC tumors in vivo. We further investigated how well EY-L sensitizes RCC cell lines and tumors toward radiation and explored the underlying mechanism of radiosensitization. Results: EY-L outperformed the corresponding single drug-loaded formulations E-L and Y-L in terms of containing primary tumor growth and improving survival in an immunocompetent syngeneic mouse model of RCC. EY-L also exhibited significantly higher sensitization of RCC cells towards radiation in vitro than E-L and Y-L. Additionally, EY-L sensitized RCC tumors towards radiation therapy in xenograft and murine RCC models. EY-L mediated induction of mitotic catastrophe via downregulation of multiple cell cycle checkpoints and DNA damage repair pathways could be responsible for the augmentation of radiation therapy. Conclusion: Taken together, our study demonstrated the efficacy of a strategic combination therapy in sensitizing RCC to radiation therapy via inhibition of DNA damage repair and a substantial increase in mitotic catastrophe. This combination therapy may find its use in the augmentation of radiation therapy during the treatment of RCC patients.

Substrate length requirements for efficient mitotic recombination in Saccharomyces cerevisiae.

An ectopic recombination system using ura3 heteroalleles varying in size from 80 to 960 bp has been used to examine the effect of substrate length on spontaneous mitotic recombination. The ura3 heteroalleles were positioned either on nonhomologous chromosomes (heterochromosomal repeats) or as direct or inverted repeats on the same chromosome (intrachromosomal repeats). While the intrachromosomal events occur at rates at least 2 orders of magnitude greater than the corresponding heterochromosomal events, the recombination rate for each type of repeat considered separately exhibits a linear dependence on substrate length. The linear relationships allow estimation of the corresponding minimal efficient processing segments, which are approximately 250 bp regardless of the relative positions of the repeats in the yeast genome. An examination of the distribution of recombination events into simple gene conversion versus crossover events indicates that reciprocal exchange is more sensitive to substrate size than is gene conversion.

The epidemiology of premenstrual symptoms in a population-based sample of 2650 urban women: attributable risk and risk factors.

This epidemiologic survey achieved a reliable measure of the prevalence of premenstrual symptoms by avoiding the biases of small or selected samples, anamnestic error, and subjective expectation. From 6232 women (a 78.8% response), aged 20-49 years, identified through a random sample of urban households, the 24-hour prevalence of symptoms was obtained using the Moos' Menstrual Distress Questionnaire, administered without reference to the menstrual cycle. For 71% of the naturally cycling women, current cycle phase was determined by follow-up (n = 2650); but a higher prevalence of severe or moderately severe affective symptoms in the premenstrual compared to the mid-cycle phase was not found. However, observed risk factor interactions led to the conclusion that premenstrual distress is a discrete mood disorder, affecting women aged 25-35 years, with probable ovulatory cycles, and vulnerable to stress; and that the risk of affective symptoms attributable to the premenstrual state was one percent.

Cancer mortality of Chinese in Canada.

Cancer deaths determined from national vital statistics in Canadian ('Chinese') immigrants who were born in mainland China, Hong Kong or Taiwan were compared with those in the Canadian-born population. Standardized mortality ratios (SMR) based on 1981 census data and on 755 deaths among 81,740 Chinese males and 586 deaths among 83,965 females during 1980-1984, showed that the overall cancer mortality in Chinese males (SMR 141), and females (SMR 116), was significantly higher than in the Canadian-born. Moreover, SMR varied by cancer site and showed a pattern of risks similar to those reported for foreign-born Chinese in the USA: strikingly high SMR for nasopharynx and liver or gallbladder in males and females; high ratios for stomach, intestines or colon, rectum, and lung, but a low ratio for prostate in males; and high ratios for lung and cervix uteri but low ratios for breast and ovary in females. These findings indicate that useful studies on cancer mortality could be carried out in Canadian Chinese.

Spontaneous foetal losses in women using different contraceptives around the time of conception.

Spontaneous losses between the 5th and 27th weeks of pregnancy were measured in a prospective study of 32 123 women whose contraceptive history around the time of conception was known. Diaphragm use prior to conception was associated with a significant reduction in second-trimester losses, after taking into account the effects of age, parity, race, marital status, alcohol use, and previous spontaneous or induced abortions. Women who used oral contraceptives and stopped them more than one month prior to their LMP experienced a deficit of first-trimester losses but conceptions occurring immediately after stopping the pill were followed by a small but nonsignificant increase in spontaneous abortions. After oral contraceptive failures there was an increase in first-trimester losses, but no change in the incidence of second-trimester ones. IUD failures were followed by a significant two-fold increase in the risk of both first and second-trimester losses: no differences were detected between the different brands.

PIP: Spontaneous losses between the 5th and 27th weeks of pregnancy were measured in a prospective study of 32,123 women whose contraceptive history around the time of conception was known. Diaphragm use prior to conception was associated with a significant reduction in second trimester losses, after taking into consideration the effects of parity, race, marital status, alcohol use, and previous spontaneous or induced abortions. Women who used (OC) oral contraceptives and then stopped them more than 1 month prior to their last menstrual period experienced a deficit of first trimester losses but conceptions occurring immediately after stopping the pill were followed by a small but nonsignificant increase in spontaneous abortion. After OC failures, there was an increase in first trimester losses, but no change in the incidence of second trimester ones. IUD failures were followed by a significant 2-fold increase in the risk of losses during the first and second trimesters with no differences detected between the different brands.

Serum protein fractions. Effects of oral contraceptives and pregnancy.

As a part of a longitudinal study to determine the side effects of oral contraceptive drugs (OCs), protein electrophoresis studies were carried out on sera obtained from 4057 current users of OCs, 9774 nonusers, and 624 women in the first trimester of pregnancy. Albumin and gamma globulin levels were lower in OC users than in nonusers; alpha-1, alpha-2, and beta fractions were higher. A similar effect was observed during the first trimester of pregnancy. The changes were temporary and reverted to normal within 12 weeks of OC withdrawal. The dosage of the estrogenic component appeared to be directly related to the lower concentration of albumin in users. The mechanisms of these changes were not well identified but very likely represent a direct effect on the metabolism of proteins.

Sex of offspring of women using oral contraceptives, rhythm, and other methods of birth control around the time of conception.

Sex ratios were studied in a cohort of 33,205 newborns whose mothers had been questioned in early pregnancy about contraceptive use around the time of conception., The proportion of males was 0.517 (95% confidence limits [CL], 0.512 to 0.522). In the 9279 offspring of women who had used oral contraceptives (OC) in the 5 months prior to conception the sex ratio was 0.517 (0.507 to 0.527). There are sufficient numbers available for study for us to be 95% certain that OC causes no shift in sex ratio of 1% or more. Women who conceived within 2 months of stopping the pill had a small excess of males (0.528; 95% CL, 0.510 to 0.546), but this excess was probably due to chance. OC failures were followed by a raised sex ratio in the offspring (0.543; 95% CL, 0.509 to 0.577), and this excess of males was observed consistently in subgroups of maternal age, parity, race, and education. Failures of rhythm contraception were also associated with a consistent excess of male births (0.567; 95% CL, 0.514 to 0.620). No changes were observed after failures of IUDs, barrier, or chemical methods.

Use of contraceptives prior to and after conception and exposure to other fetal hazards.

In a large prospective study, set up to determine whether reproductive outcomes are affected by prior contraceptive use, 34,344 women were recruited at their first antenatal visit and followed until pregnancy termination. This paper summarizes the study methods and describes the demographic differences between subjects who used various contraceptives shortly before conception, and those who experienced contraceptive failures. Thirty percent of the women had used oral contraceptives (OCs) during the 5 months prior to conception and 2.4% had continued using them after their LMP. IUDs had been used by 5.8% of women before conception and 1.1% after. If these rates are also true for the whole population of the U.S., they indicate that approximately 70,000 babies are born each year following pill-failures and 30,000 following failures of IUD's. Exposure to other fetal hazards was common, with 48% of pregnant women drinking alcohol, 28% smoking, and 15% receiving diagnostic X-rays. OC use was more common among smokers and drinkers, and OC failures were significantly associated with the use of anti-epileptics, aspirin, and with exposure to radiation.

Effects of estrogens and progestins on high density lipoproteins.

PIP: (HDL) High density liporotein levels are known to be higher in women than in men and to increase with estrogen use. To assess the effects of estrogens on HDL subspecies, analytic ultracentrifuge measurements of HDL were compared in 11 menopausal estrogen users and 16 controls. The difference in mean schlieren patterns between the groups showed a significantly higher level of HDL with flotation rate 1.5 (predominantly HDL2) in the users. This was similar to the difference in HDL seen between nonusers of hormones and age-matched males. A previous study had shown that users of combination (OCs) oral contraceptives had increased levels of HDL, suggesting that the estrogen effect on HDL is altered by the presence of added progestin. The progestin effect was studied here in more detail in 2 women with type S hyperlipoproteinemia treated with norethindrone acetate. Reduction in serum triglyceride was accompanied by a reduction in HDL, predominantly in the less dense species (HDL2). Among groups of OC and noncontraceptive estrogen and progestin users whose HDL-cholesterol levels have been reported recently, there was a direct correlation (r = 0.86, p .001) between mean HLD cholesterol and triglyceride levels. Endogenous hormonal influences on HDL were assessed by serum hormone and lipoprotein measurements at weekly intervals during 2 consecutive menstrual cycles in 4 healthy females. An increase in HDL of highest flotation rate was seen, which corresponded with the time of ovulation, raising the posibility of pituitary as well as gonadal hormone effects on HDL.^ieng

Oral contraceptive estrogen content and adverse effects.

The 1985 Health and Welfare Canada Report on Oral Contraceptives recommended oral contraceptives (OCs) containing 30-35 mcg of estrogen rather than 50 mcg as the preferred dosage for contraception. Many family physicians may regard these guidelines as mandatory when prescribing OCs, because of a presumption that pills of 50-mcg estrogen content carry a higher risk of disease. In this article, the epidemiologic evidence pertaining to a dose-response relationship between the estrogen dose of oral contraceptives and disease is critically reviewed. The review indicates that there is no incontrovertible evidence to support such a relationship. Implications of the recommendations in the Report for physicians and patients are discussed.

Malignant melanoma and oral contraceptive use among women in California.

Women who had used oral contraceptives, particularly long-term users, were found to have higher rates of malignant melanoma and of a past history of skin cancer than those who had never used oral contraceptives. This excess was confined to lesions of the lower limb. The association between oral contraceptive use and melanoma was noted in 3 separate sets of data, although it was statistically significant only in one. The possibility that this relationship is indirect because, for example, oral contraceptive users are more likely than never-users to be exposed to sunlight and thus to develop malignant melanoma, cannot be excluded.

Congenital abnormalities in the offspring of women who used oral and other contraceptives around the time of conception.

Congenital malformations were observed in 33,545 newborns whose mothers were questioned during pregnancy about contraceptives used around the time of conception. There were 597 babies (17.8/1,000) with major malformations and 4,046 (120.6/1,000) with minor ones. The 8,522 offspring of mothers who had used oral contraceptives (OC) prior to conception showed 17.2/1,000 major malformations compared with rates of 15.0 and 20.1/1,000 in the groups who had used other methods or no birth control prior to conception. There was no evidence for an increased risk of malformations in women conceiving within 1 month of stopping OC. There were 850 babies exposed to OC in utero and the ratio of observed to expected cases of major malformations was 1.24 (n.s.) if the mother was a nonsmoker and 2.98 (P = 0.028) if the mother smoked one pack or more of cigarettes daily. There were no significant changes in malformation rates following failures of intrauterine devices, spermicides or rhythm contraception.

Effect of oral contraceptive use on reoperation following surgery for Crohn's disease.

The influence of oral contraceptive (OCP) use as a risk factor for the development of Crohn's disease is disputed. We wished to determine if OCP use affected the risk of recurrence (defined as need for a second surgery) in women who had already undergone a resection for Crohn's disease. We hypothesized that if contraceptive use was a risk factor for disease development, it could influence recurrence. Using a mail questionnaire, we surveyed 138 women regarding their OCP use following surgery for Crohn's disease. All participants were between ages 16 and 35 at the time of their initial surgery which occurred between 1966 and 1984. Ninety-seven women (70%) responded. Mean follow-up was 9.9 years (range 4-27). Forty-six women required a second surgery. The recurrence rate as determined by actuarial analysis, was 27.2% (95% confidence intervals (CI95 16.5-38.1) and 58.0% (CI95 37.8-78.2) at 5 and 10 years, respectively. Thirty-two women took OCP in the first year following surgery. Eleven OCP users (34.4%) required additional surgery compared to 34 (53.1%) of nonusers. Using life table analysis, the percentage requiring a second surgery was 25.0% (CI95 6.9-43.1) and 40.7% (CI95 1.5-80%) at 5 and 10 years, respectively, for users compared to 28.4% (CI95 6.9-43.1) and 64.0% (CI95 40.5-87.5) for nonusers (Lee Desu, P greater than 0.05). When surveyed about their reasons for using OCP, most women stated that their disease did not affect their decision to use contraceptives.(ABSTRACT TRUNCATED AT 250 WORDS)

PIP: Crohn's disease (CD) is a chronic inflammatory condition affecting any area of the gastrointestinal tract from mouth to anus. This retrospective study determined the effects of oral contraceptive (OC) use on the likelihood of surgical recurrence in a cohort of patients who underwent surgery for CD. Questionnaires were mailed to 138 women who had undergone surgery for CD. Participants were 16-35 years of age. Only 97 women responded and 84 completed the second questionnaire. There were no significant differences between responders and nonresponders in terms of age at surgery, indication for surgery, and length of time in hospital. The 5-year recurrence rate was 27.2%, rising to 58.0% by 10 years. Only 32 women used OCs in the first year following surgery. With the life table analysis, the percentage requiring second surgery was 25.0% and 40.7% for users, while it was 28.4% and 64.0% for nonusers at 5 and 10 years, respectively. The majority of women reported that their disease did not constitute a major influence in their decision to use OCs. Among these women users, 10.7% were concerned about the CD risk to offspring. There were no significant differences between women with and without recurrence in terms of their reasons for using or not using OCs. Based on the results of the study, it was concluded that there was less evidence to support the hypothesis that OC use increased the risk of women requiring a second operation.

The relationship between chinook conditions and women's physical and mental well-being.

The objective of this study was (1) to determine the relationship between chinook conditions and physical and psychological symptoms in women aged 20-49 years, and (2) to examine the possibility of subgroups of chinook-sensitive women. The evidence for this relationship is at present merely anecdotal. The study carried out in 1985-1986 in Calgary comprises the secondary analysis of a large survey of various health and health-related factors, including different symptoms, of urban women aged 20-49 years. The interview date was used to link these data to days on which pre-chinook, chinook, post-chinook and non-chinook conditions occurred. Between November 1, 1985 and February 28, 1986, 182 women were interviewed on pre-chinook days, 74 on chinook days, 229 on post-chinook days and 886 on non-chinook days. Autonomic reactions and skin disorders were found to be significantly related to chinook conditions. None of the psychological symptoms was related to chinook conditions. However, a significant relationship was found between symptoms and chinook conditions in women with a history of emotional disorders. This type of information is important to educate chinook-sensitive women and health professionals as well as for hospital emergency departments in order to be able to prepare for potential increases in workload.