Effect of Probiotics for the Prevention of Acute Radiation-Induced Diarrhoea Among Cervical Cancer Patients: a Randomized Double-Blind Placebo-Controlled Study.

Radiotherapy is the mainstay treatment of cervical cancer and the most common acute side effect is radiation-induced diarrhoea (RID), which can affect up to 80% of the patients. The most frequently used probiotics for the RID in previous studies with somewhat positive results are Lactobacillus and Bifidobacterium strains. This study was aimed to investigate the effect of a probiotic containing live Lactobacillus acidophilus LA-5 plus Bifidobacterium animalis subsp. lactis BB-12 for the prevention of acute (RID) among cervical cancer patients. Patients receiving external beam pelvic radiotherapy with or without concurrent chemotherapy were randomized into probiotic or placebo groups and were double-blinded. The probiotic group received the capsules containing 1.75 billion lyophilized live bacteria to be taken one capsule three times daily beginning from the first day until the end of radiotherapy, and the placebo group received identically appearing capsules containing starch with the same schedule. Every patient received the standard dietary recommendations. The patients were assessed daily during radiotherapy and follow-up weekly for 3 weeks after radiotherapy. Total 54 patients were analyzed. The incidence of diarrhoea was reduced in the probiotic group than the placebo group (53.8 and 82.1%, p < 0.05). The mild-to-moderate and severe diarrhoea were significantly reduced in the probiotic group (p < 0.05). The use of loperamide as an anti-diarrhoeal medication was significantly reduced in the probiotic group than the placebo group (p < 0.01). The difference in grade 2 abdominal pain and episodes of abdominal pain in days were also significant (p < 0.001). Therefore, supplementation of probiotic is an easy and effective way to reduce the incidence and severity of RID in cervical cancer patients.

Targeting the cell cycle in breast cancer: towards the next phase.

Deregulation of the cell cycle is a hallmark of cancer that enables limitless cell division. To support this malignant phenotype, cells acquire molecular alterations that abrogate or bypass control mechanisms in signaling pathways and cellular checkpoints that normally function to prevent genomic instability and uncontrolled cell proliferation. Consequently, therapeutic targeting of the cell cycle has long been viewed as a promising anti-cancer strategy. Until recently, attempts to target the cell cycle for cancer therapy using selective inhibitors have proven unsuccessful due to intolerable toxicities and a lack of target specificity. However, improvements in our understanding of malignant cell-specific vulnerabilities has revealed a therapeutic window for preferential targeting of the cell cycle in cancer cells, and has led to the development of agents now in the clinic. In this review, we discuss the latest generation of cell cycle targeting anti-cancer agents for breast cancer, including approved CDK4/6 inhibitors, and investigational TTK and PLK4 inhibitors that are currently in clinical trials. In recognition of the emerging population of ER+ breast cancers with acquired resistance to CDK4/6 inhibitors we suggest new therapeutic avenues to treat these patients. We also offer our perspective on the direction of future research to address the problem of drug resistance, and discuss the mechanistic insights required for the successful implementation of these strategies.

Disruption of the anaphase-promoting complex confers resistance to TTK inhibitors in triple-negative breast cancer.

TTK protein kinase (TTK), also known as Monopolar spindle 1 (MPS1), is a key regulator of the spindle assembly checkpoint (SAC), which functions to maintain genomic integrity. TTK has emerged as a promising therapeutic target in human cancers, including triple-negative breast cancer (TNBC). Several TTK inhibitors (TTKis) are being evaluated in clinical trials, and an understanding of the mechanisms mediating TTKi sensitivity and resistance could inform the successful development of this class of agents. We evaluated the cellular effects of the potent clinical TTKi CFI-402257 in TNBC models. CFI-402257 induced apoptosis and potentiated aneuploidy in TNBC lines by accelerating progression through mitosis and inducing mitotic segregation errors. We used genome-wide CRISPR/Cas9 screens in multiple TNBC cell lines to identify mechanisms of resistance to CFI-402257. Our functional genomic screens identified members of the anaphase-promoting complex/cyclosome (APC/C) complex, which promotes mitotic progression following inactivation of the SAC. Several screen candidates were validated to confer resistance to CFI-402257 and other TTKis using CRISPR/Cas9 and siRNA methods. These findings extend the observation that impairment of the APC/C enables cells to tolerate genomic instability caused by SAC inactivation, and support the notion that a measure of APC/C function could predict the response to TTK inhibition. Indeed, an APC/C gene expression signature is significantly associated with CFI-402257 response in breast and lung adenocarcinoma cell line panels. This expression signature, along with somatic alterations in genes involved in mitotic progression, represent potential biomarkers that could be evaluated in ongoing clinical trials of CFI-402257 or other TTKis.

Coiled-coil domain containing 68 (CCDC68) demonstrates a tumor-suppressive role in pancreatic ductal adenocarcinoma.

Using integrative genomics and functional screening, we identified coiled-coil domain containing 68 (CCDC68) as a novel putative tumor suppressor gene (TSG) in pancreatic ductal adenocarcinoma (PDAC). CCDC68 allelic losses were documented in 48% of primary PDAC patient tumors, 50% of PDAC cell lines and 30% of primary patient derived xenografts. We also discovered a single nucleotide polymorphism (SNP) variant (SNP rs1344011) that leads to exon skipping and generation of an unstable protein isoform CCDC68Δ(69-114) in 31% of PDAC patients. Overexpression of full length CCDC68 (CCDC68(wt)) in PANC-1 and Hs.766T PDAC cell lines lacking CDCC68 expression decreased proliferation and tumorigenicity in scid mice. In contrast, the downregulation of endogenous CCDC68 in MIAPaca-2 cells increased tumor growth rate. These effects were not observed with the deletion-containing isoform, CCDC68Δ(69-114).

Genotranscriptomic meta-analysis of the Polycomb gene CBX2 in human cancers: initial evidence of an oncogenic role.

BACKGROUND: Polycomb group (PcG) proteins are histone modifiers known to transcriptionally silence key tumour suppressor genes in multiple human cancers. The chromobox proteins (CBX2, 4, 6, 7, and 8) are critical components of PcG-mediated repression. Four of them have been associated with tumour biology, but the role of CBX2 in cancer remains largely uncharacterised. METHODS: Addressing this issue, we conducted a comprehensive and unbiased genotranscriptomic meta-analysis of CBX2 in human cancers using the COSMIC and Oncomine databases. RESULTS: We discovered changes in gene expression that are suggestive of a widespread oncogenic role for CBX2. Our genetic analysis of 8013 tumours spanning 29 tissue types revealed no inactivating chromosomal aberrations and only 40 point mutations at the CBX2 locus. In contrast, the overall rate of CBX2 amplification averaged 10% in all combined neoplasms but exceeded 30% in ovarian, breast, and lung tumours. In addition, transcriptomic analyses revealed a strong tendency for increased CBX2 mRNA levels in many cancers compared with normal tissues, independently of CDKN2A/B silencing. Furthermore, CBX2 upregulation and amplification significantly correlated with metastatic progression and lower overall survival in many cancer types, particularly those of the breast. CONCLUSIONS: Overall, we report that the molecular profile of CBX2 is suggestive of an oncogenic role. As CBX2 has never been studied in human neoplasms, our results provide the rationale to further investigate the function of CBX2 in the context of cancer cells.

EYA4 is inactivated biallelically at a high frequency in sporadic lung cancer and is associated with familial lung cancer risk.

In an effort to identify novel biallelically inactivated tumor suppressor genes (TSGs) in sporadic invasive and preinvasive non-small-cell lung cancer (NSCLC) genomes, we applied a comprehensive integrated multiple 'omics' approach to investigate patient-matched, paired NSCLC tumor and non-malignant parenchymal tissues. By surveying lung tumor genomes for genes concomitantly inactivated within individual tumors by multiple mechanisms, and by the frequency of disruption in tumors across multiple cohorts, we have identified a putative lung cancer TSG, Eyes Absent 4 (EYA4). EYA4 is frequently and concomitantly deleted, hypermethylated and underexpressed in multiple independent lung tumor data sets, in both major NSCLC subtypes and in the earliest stages of lung cancer. We found that decreased EYA4 expression is not only associated with poor survival in sporadic lung cancers but also that EYA4 single-nucleotide polymorphisms are associated with increased familial cancer risk, consistent with EYA4s proximity to the previously reported lung cancer susceptibility locus on 6q. Functionally, we found that EYA4 displays TSG-like properties with a role in modulating apoptosis and DNA repair. Cross-examination of EYA4 expression across multiple tumor types suggests a cell-type-specific tumorigenic role for EYA4, consistent with a tumor suppressor function in cancers of epithelial origin. This work shows a clear role for EYA4 as a putative TSG in NSCLC.

SOX15 is a candidate tumor suppressor in pancreatic cancer with a potential role in Wnt/ß-catenin signaling.

Pancreatic cancer is among the top five deadliest cancers in developed countries. Better knowledge of the molecular mechanisms contributing to its tumorigenesis is imperative to improve patient prognosis. Identification of novel tumor suppressor genes (TSGs) in pancreatic cancer will reveal new mechanisms of pathway deregulation and will ultimately help improve our understanding of this aggressive disease. According to Knudson's two-hit model, TSGs are classically disrupted by two concerted genetic events. In this study, we combined DNA methylation profiling with copy number and mRNA expression profiling to identify novel TSGs in a set of 20 pancreatic cancer cell lines. These data sets were integrated for each of ∼12 000 genes in each cell line enabling the elucidation of those genes that undergo DNA hypermethylation, copy-number loss and mRNA downregulation simultaneously in multiple cell lines. Using this integrative genomics strategy, we identified SOX15 (sex determining region Y-box 15) as a candidate TSG in pancreatic cancer. Expression of SOX15 in pancreatic cancer cell lines with undetectable expression resulted in reduced viability of cancer cells both in vitro and in vivo demonstrating its tumor suppressive capability. We also found reduced expression, homozygous deletion and aberrant DNA methylation of SOX15 in clinical pancreatic tumor data sets. Furthermore, we deduced a novel role for SOX15 in suppressing the Wnt/ß-catenin signaling pathway, which we hypothesize is a pathway through which SOX15 may exert its tumor suppressive effects in pancreatic cancer.

Marijuana 'bong' smoking and tuberculosis.

The incidence of tuberculosis in the non-indigenous Australian population is low. However, in this paper we report on three cases of cavitating disease, which seem to be associated with a common illicit drug habit namely smoking marijuana using a makeshift pipe or bong. There was a total of 34 positive contacts of these cases and among the contacts sharing a bong with an index case was associated with a sixfold risk of transmission (odds ratio 6.5, confidence interval 1.4-30.4, P = 0.016). When cavitating tuberculosis is detected in a young non-indigenous native born Australian, marijuana use should be considered as a possible risk factor.

STAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury.

Signaling mechanisms that regulate astrocyte reactivity and scar formation after spinal cord injury (SCI) are not well defined. We used the Cre recombinase (Cre)-loxP system under regulation of the mouse glial fibrillary acidic protein (GFAP) promoter to conditionally delete the cytokine and growth factor signal transducer, signal transducer and activator of transcription 3 (STAT3), from astrocytes. After SCI in GFAP-Cre reporter mice, >99% of spinal cord cells that exhibited Cre activity as detected by reporter protein expression were GFAP-expressing astrocytes. Conditional deletion (or knock-out) of STAT3 (STAT3-CKO) from astrocytes in GFAP-Cre-loxP mice was confirmed in vivo and in vitro. In uninjured adult STAT3-CKO mice, astrocytes appeared morphologically similar to those in STAT3+/+ mice except for a partially reduced expression of GFAP. In STAT3+/+ mice, phosphorylated STAT3 (pSTAT3) was not detectable in astrocytes in uninjured spinal cord, and pSTAT3 was markedly upregulated after SCI in astrocytes and other cell types near the injury. Mice with STAT3-CKO from astrocytes exhibited attenuated upregulation of GFAP, failure of astrocyte hypertrophy, and pronounced disruption of astroglial scar formation after SCI. These changes were associated with increased spread of inflammation, increased lesion volume and partially attenuated motor recovery over the first 28 d after SCI. These findings indicate that STAT3 signaling is a critical regulator of certain aspects of reactive astrogliosis and provide additional evidence that scar-forming astrocytes restrict the spread of inflammatory cells after SCI.

Impact of odor from industrial hog operations on daily living activities.

Intensive industrial animal production systems worldwide require confinement of large numbers of animals in small spaces and concentration of enormous quantities of waste. Industrial hog operations, in particular, have raised public concerns about their adverse impact on public health and sustainable development. Using a community-based participatory research approach and qualitative interviews, we explored people's perception of the impact of odor from these industries on daily living activities as they relate to the beneficial use of property and enjoyment of life. Our research indicates that hog odor limits several leisure time activities and social interactions which could have adverse public health consequences. The results of this study can assist the communities and other stakeholders in public policy development that addresses these concerns.

Risk factors for agricultural injury: a case-control analysis of Iowa farmers in the Agricultural Health Study.

The purpose of this case-control study nested in the Agricultural Health Study was to assess risk factors for agricultural injury among a large group of Iowa farmers. A questionnaire sent to 6,999 farmers identified 431 cases who had a farm work-related injury requiring medical advice/treatment in the previous year and 473 controls who had no injury in the previous year. We assessed several potential risk factors for injury. A multiple logistic regression analysis showed significant associations between farm work-related injury and weekly farming work hours (> or = 50 hours/week) (OR = 1.65; 95% CI = 1.23-2.21), the presence of large livestock (OR = 1.77; 95% CI = 1.24-2.51), education beyond high school (OR = 1.61; 95% CI = 1.21-2.12), regular medication use (OR = 1.44; 95% CI = 1.04-1.96), wearing a hearing aid (OR = 2.36; 95% CI = 1.07-5.20), and younger age. These results confirm the importance of risk factors identified in previous analytic studies and suggest directions for future research in preventive intervention strategies to reduce farm work-related injuries.

Public health concerns for neighbors of large-scale swine production operations.

This article provides a review and critical synthesis of research related to public health concerns for neighbors exposed to emissions from large-scale swine production operations. The rapid industrialization of pork production in the 1990s produced a generation of confined animal feeding operations (CAFOs) of a size previously unseen in the U.S. Recent research and results from federally sponsored scientific symposia consistently indicate that neighbors of large-scale swine CAFOs can experience health problems at significantly higher rates than controlled comparison populations. Symptoms experienced by swine CAFO neighbors are generally oriented toward irritation of the respiratory tract and are consistent with the types of symptoms among interior confinement workers thathave been well documented in the occupational health literature. However, additional exposure assessment research is required to elucidate the relationship of reported symptoms among swine CAFO neighbors and CAFO emissions.

[Patients surgically treated for aortic coarctation]. / Pasienter operert for koarktasjon av aorta.

The aim of this study was to evaluate the results of surgical treatment of coarctation of the aorta. All patient files on patients operated at Haukeland Hospital, Bergen, Norway, in the period 1975-95 (n = 102) were surveyed. We sent a questionnaire to all patients alive in 1996 (n = 84), and 82 (98%) responded. Six patients (6%) died within 30 days of surgery, and 12 (12%) died later. These mortality numbers were smaller among patients operated in the period 1988-95. Among patients with associated heart defects (n = 28) the numbers were 14% and 25%, respectively. Four patients required reoperation and three patients balloon dilatation. Six of these patients were operated in the period 1975-87. Among the 82 patients that responded to the questionnaire, clinical follow-up by a cardiologist had been discontinued in 35 cases. 31 patients (38%) were not satisfied with the follow-up. Many patients reported muscle fatigue in the legs (30%), reduced exercise performance (29%), headache (26%), general fatigue (22%), and leg pain (17%). 38% did not report any symptoms. Our results are in accordance with previously reported studies, and the mortality numbers were reduced in the second period. The number of recurrences was also reduced in this period. The symptoms reported by many patients may be caused by recoarctation or an abnormal blood pressure. This group of patients should, therefore, be monitored systematically for abnormal blood pressure, recoarctation and aortic valve disease.

Scanning electron microscopy of cyclosporine-induced gingival overgrowth.

Overgrown human gingival specimens were examined histologically and by scanning electron microscopy (SEM) to study structural changes caused by cyclosporine. The biopsy specimens were from organ transplant recipients receiving cyclosporine to suppress the rejection of the transplanted organ. The epithelium of the overgrown gingiva was thickened, acanthotic and parakeratotic. Retepegs were anastomosing and extending into connective tissue. The SEM examination of the outer surface of the attached gingival showed loss of cellular attachments and cells were exfoliating. The normal honeycomb structure formed by interconnecting microvilli surrounding the pits was distorted. Outer gingival cell surface showed numerous round, ovoid and dome-like structures instead of parallel, reticular or fingerprint-like microridges. It was concluded that cyclosporine not only caused hyperplasia but also changed the structure of the outer epithelial cell surface.

The farm family perception of occupational health: a multistate survey of knowledge, attitudes, behaviors, and ideas.

It is vitally important to integrate the views and concerns of the farm family into the process of policy development. If the input is not there, policy planners could implement programs that are philosophically separated from the farm families' concerns and attitudes. This would destroy credibility and future farmer support of any new program development. From May of 1988 to April of 1989, a phone and mail survey of approximately 1,500 farmers and spouses was conducted to assess knowledge, attitudes, and behaviors regarding agricultural safety and health. The survey was conducted in Iowa, New York, South Carolina, and Washington state. Preliminary results from Iowa and New York indicated that: 1) farmers value highly, and are concerned with, occupational health and safety issues; 2) farmers report that their major concerns include stress, trauma and respiratory problems; 3) farmers would like access to an occupational health and safety service; and 4) any new farm health and safety programs must include farmer input to ensure practicality, applicability, and acceptance.