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.

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.

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.

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.

Burden of caregivers of adult patients with schizophrenia attending public health clinics in Jamaica

OBJECTIVE: To determine the extent and socio-demographic determinants of burden of care of caregivers of adult schizophrenic patients. DESIGN AND METHODS: Cross-sectional study of 115 dyads of schizophrenic patients-caregivers attending public mental health clinics, March 24 – April 4, 2014 were consecutively recruited. Burden of care was evaluated using the 22-item Zarit Burden Scale (maximum score, 88). Multiple linear regression model explored factors associated with caregiver burden. RESULTS. Caregivers were predominantly females (75.7%) and were on average 50.8 ñ 15.0 years. Most schizophrenic patients were males (65.2%) and were on average 43.6 ñ 17.2 years old. Caregivers showed on average, mild to moderate burden (score, 30.0 ñ 14.7; median, 28.0). There was a tendency for caregivers of patients who were parents or spouses to have higher levels of burden. In multivariable analyses, higher burden of caregiving was associated with inability to perform self-care, closer kinship and higher numbers of psychotic episodes in the previous year. CONCLUSIONS: Functional and social factors were important determinants of caregiver burden. Further investigations are needed which consider factors such as health status and health expenditures as predictor variables of caregiver burden.

Survival after massive ecstasy overdose.

INTRODUCTION: The toxicity profile of the amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") is well known. This designer drug is usually taken at "house parties" and may cause severe complications, sometimes leading to death, even when taken in relatively small units (1 or 2 tablets). Up to now, only a few cases of survival after ingestion of an overdose of Ecstasy have been described. In most cases the users developed hyperthermia, disseminated intravascular coagulation, rhabdomyolysis, and renal failure. CASE REPORT: We describe a man who, after ingesting 50 tablets of Ecstasy (in combination with oxazepam and alcohol) at home, recovered within 2 days. Presenting features were unconsciousness, apnea, and convulsions. It is suggested that in most cases severe 3,4-methylenedioxymethamphetamine toxicity results from an interaction between direct pharmacological effects of the drug and the prevailing environmental conditions (high ambient temperature, dancing in trance, little fluid intake).

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.

The relationship between chinook conditions and women's illness-related behaviours.

The objective of this study was to (1) to describe the relationship between chinook conditions and illness related behaviour in women, aged 20-49 years, and (2) to examine the possibility of the existence of subgroups of chinook-sensitive women. At present no empirical evidence is available regarding a relationship between chinook conditions and illness related behaviours. This study comprises the secondary analysis of a large survey of various health and health-related factors of urban women aged 20-49 years, carried out in 1985-1986 in Calgary. The interview date was used to link behaviours to chinook conditions. We found no evidence of a significant relationship between the behaviours investigated and chinook conditions in the general population. However, the data strongly supported the concept of chinook sensitivity. Women with a history of chronic health problems were more likely to visit a health care professional on chinook days than healthy women and women in the subgroup aged less than 35 years cut down their usual daily activities during chinook conditions. Women with a history of recurring migraine headaches were less likely to take prescription medication on chinook days, and women with a history of emotional disorders were more likely to have higher scores on the accident scale and to report bursts of energy or excitement during chinook days. More research is needed to identify subgroups of susceptible persons, as well as to determine whether chinook sensitive persons are equally susceptible to weather changer of other types.

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.

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 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.

Effect of cigarette smoking on recurrence of Crohn's disease.

The effect of cigarette smoking on recurrence (defined in this study as the need for repeat surgery) in patients who had previously required surgery for Crohn's disease was assessed in a historical cohort of 174 patients. Mean follow-up was 10.8 yr. The 5- and 10-yr recurrence rates were 28% and 56%, respectively. Five- and 10-yr rates were significantly different for smokers (36%, 70%) and nonsmokers (20%, 41%). When patients were stratified by gender, the increased risk was more apparent in women (odds ratio 4.2, 95% confidence interval 2.0-4.2) than in men (odds ratio 1.5, 95% confidence interval 0.8-6.0). Evidence for a dose-response relationship could be identified in women but not men. Cigarette smoking may not only be a risk factor for development of Crohn's disease but also may influence disease activity following surgery.

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.

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.

Chromosomal abnormalities in the Kaiser-Permanente Birth Defects Study, with special reference to contraceptive use around the time of conception.

Chromosomal abnormalities were studied in 33,551 abortions and births to women whose contraceptive histories had been recorded at their first antenatal visit in 1975-1977. Chromosome examinations were performed exclusively on clinical grounds. There were 45 de novo abnormalities detected (1.34/1,000); three of them were detected at amniocentesis. Trisomy 21 was observed in 27 cases (0.80/1,000), trisomy 18 in nine (0.27), other trisomies in three (0.09), and translocations or deletions in five (0.15). One case of triploidy and six cases of inherited abnormalities were detected. There were no significant racial variations. No increase in risk for chromosomal abnormalities was found among women who had used oral contraceptives prior to becoming pregnant or among women who experienced oral contraceptive breakthrough pregnancies. Two cases of trisomy 18 were observed among the 814 deliveries following oral contraceptive breakthrough conceptions (2.46/1,000), two cases of trisomy 21 occurred in 338 births following failures of rhythm contraception (5.92/1,000), and no cases of trisomy 21 or 18 among the 1,569 women using spermicides at the time of conception.

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.

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.