Protective role of thiols in carcinogen-induced DNA damage in rat liver

Biological thiols are known to play an important role in thedetoxification of xenobiotics, including chemical carcinogens.To determine the influence of cellular thiols on carcinogeninduction of hepatic DNA damage in the rat, diethylmaleate (DEM)administration was used to deplete intracellular gluta-thione(GSH). The effects of administration of the synthetic thiols,N-acetylcysteine (NAC) and alpha-mercaptopropionyl-glycine (MPG),on the induction of DNA lesions were also examined. Pretreatmentwith DEM reduced liver GSH levels by >70%. As assessed bythe technique of alkaline elution, subsequent administrationof N-methyl-N'-nitro-N-nitroso-guanidine (MNNG) resulted inDNA damage 4 h post MNNG treatment which was 4- to 8-fold greaterthan that induced in the livers of rats treated with MNNG alone.However, DEM pretreatment had little effect on the extent ofDNA damage induced by methylnitrosourea (MNU). DEM alone didnot cause any measurable DNA damage. Pretreatment with MPG orNAC reduced MNNG-induced DNA damage by as much as 77%. In contrast,MNU-induced DNA damage was increased by MPG treatment whereasNAC treatment was without effect. These results indicated thatin the rat liver, the activity of some DNA alkylating agentsmay be modulated in varying degree by the concentration of intracellularthiols. These data support the notion that thiols play an importantrole in protection against carcinogen damage, and that syntheticthiols such as MPG and NAC may be useful as anti-carcinogenicagents against certain carcinogens.     

Soft tissue sarcomas of the extremity

In 1955, in a series of abstracts entitled "A Half Century of Effort to Control Cancer," Pack and Ariel wrote, "in each individual case, there is a constant battle of judgement between the wisdom of more radical amputation and the need for preservation of that important functional part." This dilemma remains with us today. In his paper on the histogenesis of tumors, Stout, relating to the philosophy of treatment, wrote that "the best chance of curing malignant tumors of the soft tissues lies in the hands of the therapist who makes the first attempt." Pack's words are as true today as they were in 1955, and although limb salvage is possible for many patients with soft tissue sarcomas, preservation of an extremity at the risk of patient survival is not a feasible option. Most efforts at less than amputative surgery must entail multimodality therapy. Although there are some reports of success with single-agent therapy, such as surgery alone, the majority of successful, nonamputative series include surgery with radiation and/or chemotherapy. It must be emphasized that an extremely important aspect of the treatment of these patients is the judgment and evaluation by the primary physician. Therefore it is extremely important that the primary physician be familiar with the many factors involved in prognosis, both in terms of local control and of systemic illness, in order for the patient to be informed of treatment options. If this is not possible, the patient should be referred to a center that is involved in active research protocols or treatments. Although rare, the soft tissue sarcomas remain among the most difficult to treat, even though over the years there has been significant progress in diagnosis, classification, and successful local control. Patient survival is based on a multitude of factors that include the histogenesis of the tumor, its grade, size, anatomical location, the surgical procedure performed, the use of preoperative or postoperative radiation, and the clinical stage of the disease--whether it is primary or metastatic. In time, it is probable that additional factors will be found.     

Evaluating the Impact of a Novel Peer-to-Peer Educational Modality on Knowledge and Attitudes About Perinatal Mood and Anxiety Disorders

Maternal and Child Health Journal - This study assessed whether the use of a peer-to-peer educational book, written and illustrated by women who experienced common mental disorders (CMDs) in the...     

Optimizing the fellowship interview process: Perspectives from applicants and program directors of the comprehensive endocrine surgery fellowship program

BackgroundApproximately 80% of general surgery residents undertake some form of fellowship training. Our objective was to characterize goals and burdens of the interview process among applicants to Comprehensive Endocrine Surgery Fellowship programs.MethodsParticipants included trainees from 2013 to 2019. Results for ranking questions are presented as a mean rank reported out of the total number of selections.ResultsResponse rate was 54% (n = 75). The most important goal for interviews was meeting the faculty (mean rank 2.4/9), followed by “behind the scenes information” and “make a good impression” (mean rank 3.6 and 3.7, respectively). The most substantial burden for the applicant was expense (mean rank 2.1/7), followed by time away from residency (mean rank 3.1/7). The economic burden of 51% of the applicants was $2,500 to $7,500. Geographic location and expense were the top 2 reasons applicants declined offers of interviews. Despite the process, 76% of respondents indicated that no improvements to the interview process are necessary. Alternative strategies such as videoconferencing or centralized interviews received little support (<10%).ConclusionDespite identifying several burdens, survey respondents believed that in-person interviews are an integral component of the fellowship application process. Indeed, 70% of applicants do not have a first-choice program before interviews, and meeting the faculty is ranked as the greatest priority goal. Our data illustrate the importance of individual specialties evaluating and optimizing their own processes for fellowship interviews.     

ASO Visual Abstract: Chemotherapy After Diagnosis of Malignant Bowel Obstruction is Associated with Greater Survival for Medicare Patients with Advanced Malignancy

Annals of Surgical Oncology -     

PROMISE: Working with the CF community to understand emerging clinical and research needs for those treated with highly effective CFTR modulator therapy

Highly effective CFTR modulator drug therapy is increasingly available to those with cystic fibrosis. Multiple observational research studies are now being conducted to better understand the impacts of this important therapeutic milestone on long-term outcomes, patient care needs, and future research priorities. PROMISE is a large, multi-disciplinary academic study focused on the broad impacts of starting elexacaftor/tezacaftor/ivacaftor in the US population age 6 years and older. The many areas of investigation and rationale for each are discussed by organ systems, along with recognition of remaining important questions that will not be addressed by this study alone. Knowledge gained through this and multiple complementary studies around the world will help to understand important health outcomes, clinical care priorities, and research needs for a large majority of people treated with these or similarly effective medications targeting the primary cellular impairment in cystic fibrosis.     

Subtype‐specific differences in transmission cluster dynamics of HIV‐1 B and CRF01_AE in New South Wales,Australia

IntroductionThe human immunodeficiency virus 1 (HIV‐1) pandemic is characterized by numerous distinct sub‐epidemics (clusters) that continually fuel local transmission. The aims of this study were to identify active growing clusters, to understand which factors most influence the transmission dynamics, how these vary between different subtypes and how this information might contribute to effective public health responses.MethodsWe used HIV‐1 genomic sequence data linked to demographic factors that accounted for approximately 70% of all new HIV‐1 notifications in New South Wales (NSW). We assessed differences in transmission cluster dynamics between subtype B and circulating recombinant form 01_AE (CRF01_AE). Separate phylogenetic trees were estimated using 2919 subtype B and 473 CRF01_AE sequences sampled between 2004 and 2018 in combination with global sequence data and NSW‐specific clades were classified as clusters, pairs or singletons. Significant differences in demographics between subtypes were assessed with Chi‐Square statistics.ResultsWe identified 104 subtype B and 11 CRF01_AE growing clusters containing a maximum of 29 and 11 sequences for subtype B and CRF01_AE respectively. We observed a > 2‐fold increase in the number of NSW‐specific CRF01_AE clades over time. Subtype B clusters were associated with individuals reporting men who have sex with men (MSM) as their transmission risk factor, being born in Australia, and being diagnosed during the early stage of infection (p < 0.01). CRF01_AE infections clusters were associated with infections among individuals diagnosed during the early stage of infection (p < 0.05) and CRF01_AE singletons were more likely to be from infections among individuals reporting heterosexual transmission (p < 0.05). We found six subtype B clusters with an above‐average growth rate (>1.5 sequences / 6‐months) and which consisted of a majority of infections among MSM. We also found four active growing CRF01_AE clusters containing only infections among MSM. Finally, we found 47 subtype B and seven CRF01_AE clusters that contained a large gap in time (>1 year) between infections and may be indicative of intermediate transmissions via undiagnosed individuals.ConclusionsThe large number of active and growing clusters among MSM are the driving force of the ongoing epidemic in NSW for subtype B and CRF01_AE.     

Debunking Lesbian Bed Death: Using Coarsened Exact Matching to Compare Sexual Practices and Satisfaction of Lesbian and Heterosexual Women

Archives of Sexual Behavior - The current study examined the prevalence and correlates of over 50 sexual practices in a national survey of heterosexual and lesbian women in relationships. Coarsened...     

Mechanism of Intestinal Absorption of Ranitidine and Ondansetron: Transport Across Caco-2 Cell Monolayers

We have investigated the transport of ranitidine and ondansetron across the Caco-2 cell monolayers. The apparent permeability coefficients (P _app) were unchanged throughout the concentration range studied, indicating a passive diffusion pathway across intestinal mucosa. No metabolism was observed for ranitidine and ondansetron during the incubation with Caco-2 cell monolayers. P _app values for ranitidine and ondansetron (bioavailability of 50 and 100% in humans, respectively) were 1.03 ± 0.17 × 10^–7 and 1.83 ± 0.055 × 10^–5 cm/sec, respectively. The P _app value for ranitidine was increased by 15- to 20-fold in a calcium-free medium or in the transport medium containing EDTA, whereas no significant change occurred with ondansetron, indicating that paracellular passive diffusion is not rate determining for ondansetron. Uptake of ondansetron by Caco-2 cell monolayers was 20- and 5-fold higher than that of ranitidine when the uptake study was carried out under sink conditions and at steady state. These results suggest that ranitidine and ondansetron are transported across Caco-2 cell monolayers predominantly via paracellular and transcellular pathways, respectively.