Development and Characterisation of a New Patient-Derived Xenograft Model of AR-Negative Metastatic Castration-Resistant Prostate Cancer.

As the treatment landscape for prostate cancer gradually evolves, the frequency of treatment-induced neuroendocrine prostate cancer (NEPC) and double-negative prostate cancer (DNPC) that is deficient for androgen receptor (AR) and neuroendocrine (NE) markers has increased. These prostate cancer subtypes are typically refractory to AR-directed therapies and exhibit poor clinical outcomes. Only a small range of NEPC/DNPC models exist, limiting our molecular understanding of this disease and hindering our ability to perform preclinical trials exploring novel therapies to treat NEPC/DNPC that are urgently needed in the clinic. Here, we report the development of the CU-PC01 PDX model that represents AR-negative mCRPC with PTEN/RB/PSMA loss and CTNN1B/TP53/BRCA2 genetic variants. The CU-PC01 model lacks classic NE markers, with only focal and/or weak expression of chromogranin A, INSM1 and CD56. Collectively, these findings are most consistent with a DNPC phenotype. Ex vivo and in vivo preclinical studies revealed that CU-PC01 PDX tumours are resistant to mCRPC standard-of-care treatments enzalutamide and docetaxel, mirroring the donor patient's treatment response. Furthermore, short-term CU-PC01 tumour explant cultures indicate this model is initially sensitive to PARP inhibition with olaparib. Thus, the CU-PC01 PDX model provides a valuable opportunity to study AR-negative mCRPC biology and to discover new treatment avenues for this hard-to-treat disease.

Five Women American Society of Anesthesiologists Presidents: Their Lives and Careers.

This article examines the only 5 women to become presidents of the American Society of Anesthesiologists (ASA) so far. Through their personal histories, these physicians tell a collective history of women in this specialty from the 1950s to today. We trace their initial interest in medicine, medical educations and training, careers, and family lives. In doing so, the diversity of these individuals' choices and experiences emerge, and also the context in which women anesthesiologists worked. They shaped the specialty by creating new programs, addressing emerging professional problems, and mentoring successive generations. Simultaneously, they dealt with issues common to professional women in the twentieth and twenty-first centuries, such as balancing a demanding career and family.

The Prognostic, Diagnostic, and Therapeutic Potential of TRAIL Signalling in Cardiovascular Diseases.

TNF-related apoptosis-inducing ligand (TRAIL) was originally discovered, almost 20 years ago, for its ability to kill cancer cells. More recent evidence has described pleiotropic functions, particularly in the cardiovascular system. There is potential for TRAIL concentrations in the circulation to act as prognostic and/or diagnostic factors for cardiovascular diseases (CVD). Pre-clinical studies also describe the therapeutic capacity for TRAIL signals, particularly in the context of atherosclerotic disease and diseases of the myocardium. Because diabetes mellitus significantly contributes to the progression and pathogenesis of CVDs, in this review we highlight recent evidence for the prognostic, diagnostic, and therapeutic potential of TRAIL signals in CVDs, and where relevant, the impact of diabetes mellitus. A greater understanding of how TRAIL signals regulate cardiovascular protection and pathology may offer new diagnostic and therapeutic avenues for patients suffering from CVDs.

Expression of Minichromosome Maintenance Protein 2 (MCM2) in Oral Epithelial Dysplasia and Oral Squamous Cell Carcinoma: A Systematic Review.

The histopathological investigations of oral lesions are a basic approach for diagnosing ongoing cancer or pre-cancer associated pathological attributes in the dissected biopsy. The early detection and management of potentially malignant disorders of the lip and oral cavity that require intervention may reduce malignant transformations, or in case any malignancy is detected during surveillance, the appropriate treatment may improve survival rates. This would guide the clinicians to decide the appropriate treatment modality or lesion to achieve a more favorable prognosis. MCM2 protein is involved in DNA replication providing additional information about the prognosis of neoplasms. Some authors have pointed out that MCM proteins have been inversely correlated with salivary tumour differentiation and therefore could be an indicator of proliferation potential. Therefore, it is essential to find the expression of the MCM2 gene in oral leukoplakia and oral squamous cell carcinoma. Electronic databases like Ebscohost, Livivo, Google Scholar and PubMed were searched. Based on the inclusion and exclusion criteria, 2 reviewers (MS and SN) independently selected the relevant articles. Any disagreement was discussed until a consensus was reached. We used the QUADAS-2 tool to assess the quality of the included studies over four key domains: patient selection, index test, reference standard and flow and timing of participants through the study. 10 out of 57 titles were found to meet the eligibility criteria. Biopsied tissue with immunohistochemical staining or advanced diagnostic studies were included. A total of 901 samples were included in the study and different groups were normal oral mucosa (NOM), oral epithelial dysplasia (OED) and oral squamous cell carcinoma (OSCC). MCM2 proteins are useful diagnostic markers for distinguishing malignant from benign epithelial dysplasia and for early detection and diagnosis of OSCC as an adjunct to clinicopathological parameters. Supplementary Information: The online version contains supplementary material available at 10.1007/s12070-022-03296-7.

Asymptomatic bacteriuria of pregnant women in a tertiary care centre.

BACKGROUND: Asymptomatic bacteriuria (ASB) is commonly seen during pregnancy due to the various morphological, hormonal, and physiological changes the body undergoes. If left undiagnosed, it can lead to conditions such as pyelonephritis and preterm delivery which could culminate in causing maternal and fetal morbidity and mortality. Therefore, this study aims to determine the prevalence, risk factors, microbial profile, and antibiotic susceptibility patterns associated with ASB in a tertiary healthcare center. MATERIALS AND METHODS: A cross-sectional study was carried out where 150 urine samples were obtained from pregnant women within the gestational age of 13-36 weeks. Randomized stratified sampling was the method of sampling used. A questionnaire was also administered to them to determine potential risk factors. The samples were cultured and identified using biochemical tests. Antibiotic susceptibility tests were carried out by Kirby-Bauer disc diffusion method. Statistical analysis was carried out using Chi-square test. The graphs and tables were generated using Microsoft Excel and Word. RESULTS: Out of the 150 samples that were obtained, 8 samples had significant bacteriuria which is a prevalence of 5.33%. Escherichia coli was the most frequently isolated organism accounting to 45% of the isolates. The other organisms that were isolated were Enterococcus, Klebsiella pneumoniae, Coagulase negative staphylococcus (CONS), Candida albicans, and Group B Streptococcus which measured to 11% of the total distribution each. In the antibiotic sensitivity tests, among the gram-negative isolates, marked resistance to Ampicillin and Amoxycillin along with sensitivity to Cotrimoxazole and Nitrofurantoin. Of the gram-positive isolates, there was sensitivity to Ampicillin and Nitrofurantoin. A positive correlation was seen between the age groups of 23-27 and the prevalence of ASB. CONCLUSION: The prevalence of ASB in this study shows that ASB is not uncommon in the population. Despite the World Health Organization (WHO) guidelines and National Health Mission recommendations to make urine check-ups a routine, it not carried out, possibly due to cost implications. However, it poses a risk for severe maternal and fetal outcomes and hence, should be screened for on a regular basis. Thus, this study emphasizes the importance of screening pregnant women for ASB for promoting better maternal and fetal health.

Surgical operations at Massachusetts General Hospital in 1846 and 1847: Early impact of the discovery of anaesthesia.

The introduction of anaesthesia on 16 October 1846 brought about tremendous changes in the discipline of surgery. We sought to determine whether the concept of painless surgery was accepted by practitioners and patients, and whether this led to an increase in frequency and variety of surgical operations performed. To study these changes, we analysed surgical records from Massachusetts General Hospital, Boston, Massachusetts (MGH) in the months surrounding the discovery of ether anaesthesia. Surgical records from MGH between 25 February 1846 and 14 March 1847 were examined, and the variables studied included number of operations, type of operations, patient demographics, complications and analgesics used, as well as comments made by surgeons. Immediately following the introduction of anaesthesia, MGH experienced a sizeable increase in the volume of surgical operations. This included a doubling in the percentage of female patients undergoing surgery. Orthopaedic procedures and amputations both increased in frequency, as did the number of surgeons operating. Several records indicated the presence of postoperative wound infection. Operations were still performed without anaesthesia. Following the introduction of ether anaesthesia in 1846, surgical volume increased, and more women underwent surgery. This suggests early acceptance of anaesthesia by patients and the medical profession. In an era prior to the introduction of antiseptic and aseptic techniques it is not surprising that wound infections were observed in several patients. We provide a glimpse of anaesthesia and surgery during the first few months after the first public demonstration of anaesthesia at MGH.

An artificial neural network combined with response surface methodology approach for modelling and optimization of the electro-coagulation for cationic dye.

An artificial neural network (ANN) approach with response surface methodology (RSM) technique has been applied to model and optimize the removal process of Brilliant Green dye by batch electrocoagulation process. A multilayer perceptron (MLP) - ANN model has been trained by four input neurons which represent the reaction time, current density, pH, NaCl concentration, and two output neurons representing the dye removal efficiency (%) and electrical energy consumption (kWh/kg). The optimized hidden layer neurons were obtained based on a minimum mean squared error. The batch electrocoagulation process was optimized using central composite design with RSM once the ANN network was trained and primed to anticipate the output. At optimized condition (electrolysis time 10 min, current density 80 A/m2, initial pH 5 and electrolyte NaCl concentration 0.5 g/L), RSM projected decolorization of 98.83% and electrical energy consumption of 14.99 kWh/kg. This study shows that the removal of brilliant green dye can be successfully carried out by a batch electrocoagulation process. Therefore, the process is successfully trained by ANN and optimized by RSM for similar applications.

Henry Jacob Bigelow (1818-1890): A Champion for Anesthesia and Catalyst for the Advancement of Surgery.

Prior to the advent of anesthesia, surgery was limited in scope due to the excruciating pain experienced by patients. This raised challenges for surgeons who were distressed by the inadvertent suffering caused by surgery. The first successful use of ether anesthesia by William Thomas Green Morton (1819-1868) in 1846 at Massachusetts General Hospital was a turning point for the profession. The innovation and proliferation of operations catalyzed by the introduction of anesthesia altered the landscape of surgical practice. Initially, the introduction of ether into the field was met with hesitation and resistance by several parties in the medical field. It took the efforts of prominent surgeons to ensure that ether achieved its full potential. The greatest supporter of ether during this epoch was the young surgeon Henry Jacob Bigelow (1818-1890), who spent 30 years of his career advocating for and experimenting with anesthesia. The efforts of Bigelow, a gifted surgeon renowned for his contributions to orthopedic surgery, were instrumental in the promotion of anesthesia and the advancement of the surgical profession. In this article, we discuss the life, career, and contributions of Bigelow, particularly in the context of the introduction of modern anesthesia.

Microenvironment drives cell state, plasticity, and drug response in pancreatic cancer.

Prognostically relevant RNA expression states exist in pancreatic ductal adenocarcinoma (PDAC), but our understanding of their drivers, stability, and relationship to therapeutic response is limited. To examine these attributes systematically, we profiled metastatic biopsies and matched organoid models at single-cell resolution. In vivo, we identify a new intermediate PDAC transcriptional cell state and uncover distinct site- and state-specific tumor microenvironments (TMEs). Benchmarking models against this reference map, we reveal strong culture-specific biases in cancer cell transcriptional state representation driven by altered TME signals. We restore expression state heterogeneity by adding back in vivo-relevant factors and show plasticity in culture models. Further, we prove that non-genetic modulation of cell state can strongly influence drug responses, uncovering state-specific vulnerabilities. This work provides a broadly applicable framework for aligning cell states across in vivo and ex vivo settings, identifying drivers of transcriptional plasticity and manipulating cell state to target associated vulnerabilities.

A decoy strategy to activate the immune system.

An approach comprising a novel fusion protein and inactivated virus, as a more efficacious vaccine against invading viruses is presented, using SARS-CoV-2 as a most prominent example. The fusion protein consists of the Hepatitis B surface antigen (HBsAg) conjugated to the N-terminal helix (NTH) of Angiotensin-Converting Enzyme 2 (ACE2), which is the receptor for SARS-CoV-2. For vaccination, this fusion protein is to be administered together with the whole killed virus. The NTH would bind to the Receptor Binding Domain (RBD) of the Spike protein of the killed virus. Due to HBsAg acting as a decoy, immune responses would be mounted. Neutralizing antibodies (NAbs) pre-existing in people already vaccinated with the recombinant Hepatitis B vaccine, fresh production of NAbs, and NAbs produced by memory B cells would bind to the HBsAg. This would lead to "presentation" of the killed virus to elements of the immune system at close range. Also, there would be enhanced opsonization and effective antigen presentation. This two-component vaccine could be a platform strategy, wherein HBsAg could be linked to the part of the cellular receptor that any new intractable virus binds to, and is administered together with whole inactivated virus. Now, the same fusion protein, administered by itself to persons with infection, would have therapeutic action, yet by harnessing elements of the immune system. NAbs would bind to the fusion protein as above, the NTH of which would bind to the RBDs of the infecting virus, which, in effect would be neutralized.

The Origins, Evolution, and Spread of Anesthesia Monitoring Standards: From Boston to Across the World.

In the mid-1980s, the anesthesia departments at hospitals affiliated with Harvard Medical School were faced with a challenge: mounting medical malpractice costs. Malpractice insurance was provided by the Controlled Risk Insurance Company (CRICO), a patient safety and medical malpractice insurance company owned by and providing service to the Harvard medical community. CRICO spearheaded an effort to reduce these costs and ultimately found a way to decrease the risks associated with anesthesia. Here, we chronicle events that led to the dramatic changes in medical practice that resulted from the activities of a small group of concerned anesthesiologists at Harvard-affiliated hospitals. We place these events in a historical perspective and explore how other specialties followed this example, and end with current strategies that minimize the risk associated with anesthesia. We conducted interviews with principals who formulated original standards of patient monitoring. In addition, we consulted documents in the public domain and primary source material. Efforts of these pioneers resulted in the establishment of the seminal Harvard-based anesthesia monitoring standards for minimal monitoring. What followed was an unprecedented transformation of the entire field. After the implementation of these standards at Harvard-affiliated hospitals, the American Society of Anesthesiologists (ASA) adopted "Standards for Basic Anesthetic Monitoring" for use during the administration of all anesthetics in the United States. Other nations have since adopted similar guidelines and these practices have resulted in significant improvements in patient safety. Currently, we estimate mortality due to anesthesia in healthy patients to be 1:400,000-perhaps as much as 10 times lower since the early 1980s. What began as an attempt to lower medical malpractice costs in a group of university hospitals became a worldwide effort that resulted in improvements in patient safety. Other specialties have adopted similar measures. Currently, an attitude and appreciation of safety are exemplified by several practices that include among others-the adherence to these patient safety guidelines, simulator training, the promulgation of standards and guidelines by ASA, and the use of a safety checklist before induction of anesthesia.

The French Academy of Sciences: Deliberations related to the discovery of anaesthesia.

In the mid-19th century, the French Academy of Sciences was one of the oldest and most prominent scientific institutions in the world. Individuals seeking credit for the discovery of surgical anaesthesia contacted the French academy to achieve recognition from this prestigious body of scientists and to spread news of the discovery throughout continental Europe. The French Academy of Sciences was established under the reign of King Louis XIV in 1666 with the goal of supporting and advancing scientific research. Membership was limited to the most accomplished French scientists, who presented their research at weekly meetings and advised the French government on scientific matters. The academy began their deliberations on the discovery of anaesthesia in January 1847. Since anaesthesia had already been tested in the United States and Great Britain, the main contributions of the French academy deliberations included refining administration techniques and documenting the effects of anaesthesia on animals and humans. Recognition of surgical anaesthesia by the French Academy of Sciences and the swift adoption of its use in surgical practice throughout the country lent credibility to this new discovery and enabled the discipline of surgery to progress. Nevertheless, the academy was not able to solve the initial problem for which they may have been contacted-the dispute about which individual deserved credit for the discovery of anaesthesia.

The PTEN Conundrum: How to Target PTEN-Deficient Prostate Cancer.

Loss of the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN), which negatively regulates the PI3K-AKT-mTOR pathway, is strongly linked to advanced prostate cancer progression and poor clinical outcome. Accordingly, several therapeutic approaches are currently being explored to combat PTEN-deficient tumors. These include classical inhibition of the PI3K-AKT-mTOR signaling network, as well as new approaches that restore PTEN function, or target PTEN regulation of chromosome stability, DNA damage repair and the tumor microenvironment. While targeting PTEN-deficient prostate cancer remains a clinical challenge, new advances in the field of precision medicine indicate that PTEN loss provides a valuable biomarker to stratify prostate cancer patients for treatments, which may improve overall outcome. Here, we discuss the clinical implications of PTEN loss in the management of prostate cancer and review recent therapeutic advances in targeting PTEN-deficient prostate cancer. Deepening our understanding of how PTEN loss contributes to prostate cancer growth and therapeutic resistance will inform the design of future clinical studies and precision-medicine strategies that will ultimately improve patient care.

The rise and fall of heterologous transfusion.

Now a routine lifesaving treatment, blood transfusion between humans became a safe procedure only after many early therapeutic disasters. Performed between different species, heterologous transfusions actually succeeded homologous transfusions, those performed between members of the same species. In the early history of transfusion, both homologous and heterologous transfusions were performed in many clinical settings. Early clinicians were unable to distinguish between deaths caused by baseline illness and those resulting from transfusions. This report examines both early experiments with homologous transfusion between animals and later efforts investigating and finally abandoning heterologous transfusion. Topics explored include: 1) contributions and lessons learned from key individuals, 2) how these researchers suggested, performed, advocated, or challenged the practice of heterologous transfusion, and 3) why heterologous transfusions were even considered as a mode of therapy.

Julia Gordon Arrowood (1900 - 1984): A Brilliant Anesthesiologist and a Woman of Many Firsts in Medicine.

After a brief "golden age" in the late 1800s, the patriarchal establishment fought back and women faced increasing restrictions in practicing medicine. In 1900, 18.2% of all physicians in the city of Boston were women, but this number decreased to 8.7% by 1930. The relatively young field of anesthesiology was one of the more welcoming specialties for women during this time. History has been unkind to these early female trailblazers who have often been overlooked in favor of the men in their fields. Julia Gordon Arrowood (1900-1984) was a forerunner for women in medicine and a prominent anesthesiologist in Boston from the 1930s until the 1950s. Her work included not only clinical medicine, but also research and teaching. She attended Boston University School of Medicine, graduating as valedictorian in the class of 1933. She interned at Belmont Hospital in Worcester, MA where she decided on a career in anesthesiology. She was accepted as a resident at Massachusetts General Hospital (MGH) by chief-anesthetist Henry Beecher in 1935, thereby becoming the first woman anesthesiology resident in Massachusetts. She remained at MGH and was named Acting Chief of Anesthesia in 1943. In 1944, she became president of the New England Society of Anesthesiologists, another first for a woman. In 1946, she joined Reginald Smithwick's team as Chief of Anesthesia at Massachusetts Memorial Hospital, Boston, and concurrently held the position of Professor of Anesthesiology at Boston University School of Medicine. Arrowood led many of the earliest studies on spinal anesthesia, muscle relaxants, and spinal headaches. In 1957, she moved to Kentucky and joined the United Mine Workers hospital system where she worked until her retirement in 1970. Women such as Julia Arrowood remain underrepresented in the annals of the history of medicine. Much work is needed to recognize the many contributions made by women physicians and to provide equal opportunities, pay, and status.

TRAIL signals, extracellular matrix and vessel remodelling.

The extracellular matrix (ECM) is an essential part of the vasculature, not only providing structural support to the blood vessel wall, but also in its ability to interact with cells to regulate cell phenotype and function including proliferation, migration, differentiation and death - processes important in vascular remodelling. Increasing evidence implicates TNF-related apoptosis-inducing ligand (TRAIL) signalling in the modulation of vascular cell function and remodelling under normal and pathological conditions such as in atherosclerosis. TRAIL can also stimulate synthesis of multiple ECM components within blood vessels. This review explores the relationship between TRAIL signals, the ECM, and its implications in vessel remodelling in cardiovascular disease.

A "Western Diet" promotes symptoms of hepatic steatosis in spontaneously hypertensive rats.

Systemic hypertension, characterized by elevated blood pressure ≥140/90 mm Hg, is a major modifiable risk factor for cardiovascular disease. Hypertension also associates with non-alcoholic fatty liver disease (NAFLD), which is becoming common due to a modern diet and lifestyle. The aim of the present study was to examine whether a high-fat "Western" diet had effects on hypertension and associated NAFLD. Normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were placed on a normal chow or high-fat diet for 8 weeks; blood pressure was measured fortnightly and body weight recorded weekly. As expected, SHR had elevated blood pressure compared to WKY. Diet did not influence blood pressure. Compared to SHR, WKY rats gained more weight, associating with increased white adipose tissue weight. Normotensive rats also had higher plasma cholesterol and triglycerides in response to a "Western" diet, with no changes in plasma glucose levels. Neither strain developed atherosclerosis. Interestingly, high-fat diet-fed SHR had increased liver weight, associating with a significant level of hepatic lipid accumulation not observed in WKY. Further, they exhibited hepatocellular ballooning and increased hepatic inflammation, indicative of steatohepatitis. These findings suggest that a high-fat "Western" diet promotes features of NAFLD in SHR, but not WKY rats. Importantly, the high-fat diet had no effect on blood pressure.

The PI3K-AKT-mTOR Pathway and Prostate Cancer: At the Crossroads of AR, MAPK, and WNT Signaling.

Oncogenic activation of the phosphatidylinositol-3-kinase (PI3K), protein kinase B (PKB/AKT), and mammalian target of rapamycin (mTOR) pathway is a frequent event in prostate cancer that facilitates tumor formation, disease progression and therapeutic resistance. Recent discoveries indicate that the complex crosstalk between the PI3K-AKT-mTOR pathway and multiple interacting cell signaling cascades can further promote prostate cancer progression and influence the sensitivity of prostate cancer cells to PI3K-AKT-mTOR-targeted therapies being explored in the clinic, as well as standard treatment approaches such as androgen-deprivation therapy (ADT). However, the full extent of the PI3K-AKT-mTOR signaling network during prostate tumorigenesis, invasive progression and disease recurrence remains to be determined. In this review, we outline the emerging diversity of the genetic alterations that lead to activated PI3K-AKT-mTOR signaling in prostate cancer, and discuss new mechanistic insights into the interplay between the PI3K-AKT-mTOR pathway and several key interacting oncogenic signaling cascades that can cooperate to facilitate prostate cancer growth and drug-resistance, specifically the androgen receptor (AR), mitogen-activated protein kinase (MAPK), and WNT signaling cascades. Ultimately, deepening our understanding of the broader PI3K-AKT-mTOR signaling network is crucial to aid patient stratification for PI3K-AKT-mTOR pathway-directed therapies, and to discover new therapeutic approaches for prostate cancer that improve patient outcome.

Vascular transcriptome landscape of Trail-/- mice: Implications and therapeutic strategies for diabetic vascular disease.

Circulating plasma TRAIL levels are suppressed in patients with cardiovascular and diabetic diseases. To identify novel targets in vascular metabolic diseases, genome-wide transcriptome of aortic tissue from Trail-/- versus Trail+/+ mice were interrogated. We found 861 genes differentially expressed with TRAIL deletion. Gene enrichment analyses showed many of these genes were related to inflammation, cell-to-cell cytoskeletal interactions, and transcriptional modulation. We identified vascular protective and pathological gene clusters, with Ifi205 as the most significantly reduced vascular protective gene, whereas Glut1, the most significantly increased pathological gene with TRAIL deletion. We hypothesized that therapeutic targets could be devised from such integrated analysis and validated our findings from vascular tissues of diabetic mice. From the differentially expressed gene targets, enriched transcription factor (TF) and microRNA binding motifs were identified. The top two TFs were Elk1 and Sp1, with enrichment to eight gene targets common to both. miR-520d-3p and miR-377-3p were the top enriched microRNAs with TRAIL deletion; with four overlapping genes enriched for both microRNAs. Our findings offer an alternate in silico approach for therapeutic target identification and present a deeper understanding of gene signatures and pathways altered with TRAIL suppression in the vasculature.