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Background. Postmenopausal hirsutism could be due to a myriad of causes, including ovarian and adrenal tumours, ovarian hyperthecosis, exogenous androgens, and Cushing's syndrome. We report a patient who was found to have a rare cause of postmenopausal hirsutism. Case Presentation. A 64-year-old postmenopausal woman with a history of hypertension, thyrotoxicosis, and poorly controlled diabetes on multiple oral hypoglycaemic agents presented with gradual onset progressive excessive hair growth without any virilizing features. On examination, she did not have Cushingnoid features or clitoromegaly. Her hirsutism was quantified with Ferriman–Gallwey score which was 9. Her biochemical evaluation showed elevated testosterone levels with normal DHEAS, ODST, 17-OHP, and prolactin. Low-dose dexamethasone suppression test did not suppress testosterone more than 40%. Contrast-enhanced CT of the adrenal and pelvis did not show any adrenal or ovarian mass lesions. Transvaginal ultrasound scan showed bilateral prominent ovaries only. Combined adrenal and ovarian venous sampling was carried out to localize the source of excess androgen, but only the left adrenal vein was successfully cannulated which showed suppressed testosterone level compared to periphery. The patient underwent total abdominal hysterectomy and bilateral salphingo oophorectomy, and her testosterone level normalized postoperatively. Her glycaemic control improved. Histology showed evidence of bilateral diffuse ovarian Leydig cell hyperplasia. Conclusion. Evaluation of postmenopausal hirsutism needs careful history and examination followed by biochemical evaluation and imaging. While adrenal and ovarian venous sampling can help to arrive at a diagnosis, it is a technically demanding procedure with low success rates even at centers of excellence. Therefore, in such situations, bilateral oophorectomy may be the best course of action which will give the histological confirmation of the diagnosis. Successful treatment of hyperandrogenism can result in improvement of glycaemic control. Bilateral diffuse Leydig cell hyperplasia is a rare but important cause of postmenopausal hirsutism. [ABSTRACT FROM AUTHOR]

Background. Polycystic ovary syndrome (PCOS) is a common endocrine disorder with heterogeneous etiology. Typical features consist of oligo/anovulation, polycystic ovaries, and features of hyperandrogenism. Pathogenesis is multifactorial, and positive family history may have a predisposition for disease development. The syndrome is associated with multiple metabolic and nonmetabolic entities. As the disease is involved with multiple adverse outcomes, the successful treatment is pivotal. Among the more advanced options, the unilateral oophorectomy is considered as a last resort to alleviate the symptoms. Case Presentation. A 29-year-old female presented to us with oligomenorrhea, severe hirsutism, androgenic pattern hair loss, acne, increased skin pigmentation, and secondary subfertility. On examination, she was obese with a body mass index (BMI) of 29.6 kg/m2. She had evidence of acanthosis nigricans, androgenic pattern balding, acne, dorsal, supraclavicular fat deposition, and moderate-severe hirsutism. Investigations confirmed excess right ovarian testosterone secretion which led to the ultimate management with right oophorectomy with successful alleviation of clinical features. Conclusions. The multifaceted medical treatment comprises the first-line therapy in PCOS. Surgery is considered as a second-line option in resistant PCOS following failure of initial therapeutic options. We report a case of resistant polycystic ovary syndrome with secondary subfertility and moderate-to-severe hirsutism who was successfully treated with unilateral oophorectomy with favorable results. [ABSTRACT FROM AUTHOR]

The home remedy of taking honey along with a citrus juice of lemon, lime or calamansi to soothe sore throat has long been practiced in many cultures across the world, since ancient times. This paper aims to systematically review the antibacterial effect of honey and citrus juice on Streptococcus pyogenes by means of a systematic search in EBSCOhost, Medline, Scopus and ISI Web of Science databases for reports of studies investigating the antibacterial effects of honey and citrus fruit juice on S. pyogenes. A total of 415 publications were initially identified, out of which, 20 were finally chosen and reviewed by looking at the tittles, abstracts and full paper using pre-determined inclusion and exclusion criteria in relation to honey (n=16) and citrus (n=4). The majority of the studies showed that both honey and citrus have significant antimicrobial effect on S. pyogenes. There are still not many available data though on the combined effect of honey and citrus on the bacterium. This knowledge gap offers an opportunity to investigate those effects with the purpose of supporting traditional practice with scientific evidences. [ABSTRACT FROM AUTHOR]

Introduction: Older patients with cancer often face increased risks of adverse reactions and complications when undergoing systemic therapy. In 2020, the Townsville Cancer Centre in North Queensland established a nurse navigator led geriatric oncology service for patients aged 75 years and above referred for systemic therapy for solid organ malignancy. This study sought to evaluate the safety outcomes and trends in the administration of systemic therapy in older patients following the introduction of this service., Materials and Methods: A retrospective study was conducted at a single centre, focusing on patients aged 75 years and above referred for chemotherapy or immunotherapy for solid organ malignancies. Patients referred after the implementation of the service were classified as the geriatric assessment cohort, while those referred before were categorized as the historical cohort. Outcome measures included unplanned hospital admissions, duration of hospital stays, rates of systemic therapy de-escalation, and frailty identified during geriatric assessments., Results: The study included 129 patients, with 60 in the geriatric assessment cohort and 69 in the historical cohort. The geriatric assessment cohort exhibited a significant decrease in both the average number of hospital admissions per patient compared to the historical cohort (0.59 vs. 1.13, p = 0.01) and the average length of hospital stay (4.3 days vs. 6.7 days, p = 0.04). Rates of systemic therapy de-escalation were comparable between the two cohorts (47 % vs. 59 %, p = 0.16). Frailty was frequently identified during geriatric assessments, requiring intervention both before and during treatment., Discussion: Our two-year observation of the nurse navigator-led geriatric oncology model suggests that it contributed to improved safety outcomes, leading to reductions in unplanned hospitalizations and lengths of hospital stays, without significant changes in the rates of de-escalated systemic therapy., Competing Interests: Declaration of Competing Interest There are no conflicts of interest to declare from any author., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Young-onset diabetes (YOD) is characterised by unique diagnostic and management challenges more pronounced in resource-limited settings like Sri Lanka. Aims: We aimed to ascertain the prevalence, patterns and characteristics of YOD in Sri Lanka and describe the state of care. Methods: Retrospective review of baseline data of all patients enrolled in the prospective multicentre Database for Young-Onset Diabetes, Sri Lanka (DYOD-SL), was performed, from April 2021 to April 2023. Results: A total of 2531 patient data were included from 28 centres island-wide. Females were 57.6%. The median age was 20 years (interquartile range (IQR) 17, 23), and the age at diagnosis was 15 years (IQR 12, 18). Type 1 diabetes (T1D) was the commonest (57.6%), followed by Type 2 diabetes (T2D) at 34.3%. Younger age at disease onset ( p < 0.001), lower BMI ( p < 0.001), and diabetic ketoacidosis (DKA) at presentation ( p < 0.001) favoured T1D. In the total cohort, the median HbA1c was 9.8% (IQR 7.8, 12.1) with younger patients having poorer control ( p = 0.001). Prevalence of nephropathy was 8.1%, retinopathy was 6.6%, neuropathy was 4.1%, moderate-high-risk diabetic foot disease was 1.9%, and macrovascular complications were 0.5%. Hypertension and dyslipidaemia occurred in 2.7% and 14%, respectively. Among patients > 18 years, overweight and obese were 22.2% and 10.4%. Corresponding prevalence in the 5-18-year age group was 20% and 14.7%. Among the insulin users (76%) in the total cohort, the majority (64.7%) were on premixed-based insulin regimens delivered by syringes. Self-monitoring of blood glucose (BG) was reported in 71.3% of the total population. None were on continuous/flash glucose monitoring or insulin pumps. Conclusion: T1D was the commonest subtype of YOD in this hospital-based population. However, T2D was notably higher and is of significant concern. Overall, suboptimal glycaemic control and high rate of complications were noted along with substandard insulin regimens and BG monitoring., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Maulee Hiromi Arambewela et al.)

Background: The optimal care pathway (OCP) for people with breast cancer provides a framework for investigation and management of patients with breast cancer, with delays previously identified regionally., Aim: With emphasis on the neoadjuvant pathway, the primary aim of this study was to assess the practicality of implementing the breast cancer OCP timeframes regionally in comparison to nationally referenced standards., Methods: A retrospective institutional audit was performed for patients undergoing neoadjuvant therapy for breast cancer. The time from referral to specialist review, completion of investigations, discussion at multidisciplinary team (MDT) meetings, initiation of neoadjuvant chemotherapy (NACT) and surgery were calculated and compared to OCP., Results: Fifty-three patients were included, with 19 patients living rurally (36%). Twenty-four patients (45%) were seen by a specialist surgeon within 2 weeks of referral. Following surgical review, 44 patients (83%) completed investigations within 2 weeks, and 43 patient cases (81%) were discussed at MDT meetings within 2 weeks. Forty-eight patients (91%) were commenced on neoadjuvant treatment within 4 weeks of decision to treat, and 43 patients (81%) underwent surgery within 6 weeks of neoadjuvant treatment completion. Delays from initial referral to NACT were more frequent in rural patients compared to urban (79% vs 94%, P < 0.05)., Conclusion: Adherence to OCP timeframes for patients undergoing neoadjuvant therapy in a regional centre was feasible and strategies are needed to bridge gaps identified for rural patients., (© 2024 Royal Australasian College of Physicians.)

Aims and Method: The aim of this project was to set out recommendations for the section 17 leave form to reflect guidance provided in the Mental Health Act 1983: Code of Practice, following local Care Quality Commission feedback. We reviewed guidance in the Code and publicly available leave forms to identify items to include in the leave form. Then, we determined which publicly available leave forms included each item and reviewed whether the item should be included in the leave form and whether any reformulation was needed., Results: Using the method described, we identified a list of items that should be included in the leave form. When comparing the leave forms of different trusts, there was considerable variation with respect to which items were included in each form., Clinical Implications: We provide some recommendations for future practice regarding section 17 leave forms to facilitate consistency with the Code and between different trusts.

Hyponatraemia is an uncommon complication of external biliary drainage. We report on a 62-year-old male with hilar cholangiocarcinoma who developed refractory severe hyponatraemia despite sodium replacement during preoperative external biliary drainage. Nasojejunal bile refeeding restored sodium levels to normal., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Purpose: There is an emerging role of the use of Prostate-Specific Membrane Antigen (PSMA) Positron Emission Tomography (PET) in renal cell carcinoma. Herein, we report our experience in use of PSMA PET in recurrent or metastatic renal cell carcinoma (RCC)., Methods: A retrospective analysis of all patients who underwent PSMA PET for suspected recurrent or de-novo metastatic RCC between 2015 and 2020 at three institutions was performed. The primary outcome was change in management (intensification or de-intensification) following PSMA PET scan. Secondary outcomes included histopathological correlation of PSMA avid sites, comparison of sites of disease on PSMA PET to diagnostic CT and time to systemic treatment., (© 2023. The Author(s).)

Breast cancer remains a significant cause of mortality in females worldwide, despite advances in technology and treatment. MicroRNA expression in breast cancer is studied both as potential biomarkers and for therapeutic purposes. Accumulated evidence revealed microRNA profile of various types of cancer cells following antineoplastic treatment. The progression of research in this area provides better understanding on the anti-cancer mechanism of various natural compounds and drugs specifically on the microRNA regulation. Hence, we aim to systematically review differentially expressed microRNA in MCF-7, a commonly studied breast cancer cell line, after treatment with anti-neoplastic agents. Relevant keywords were used to screen for research articles that reported on the differentially expressed microRNAs in experimental models of MCF-7 before and after anti-neoplastic treatment. Target genes of microRNAs were identified from MiRTarbase and further in silico functional analysis of the target genes were performed using DAVID bioinformatic resources. Two upregulated microRNAs (mir-200c and let-7d) and 3 downregulated microRNAs (mir-27a, mir-27b and mir-203) were identified by highest number of studies. Three microRNAs (let-7a, mir-23a and mir-7) showed inconsistent direction of expression. Genes functional analysis revealed the regulatory effect of microRNA on genes related to angiogenesis, hypoxia, P53, FoxO and PI3K-AKT signalling. Clusters of genes associated to the pathway of angiogenesis, cancers, cell proliferation and apoptosis were noted through protein-protein interaction analysis. MicroRNAs, especially the mir-200c, let-7d, mir-27a, mir-27b and mir-203 from this review could be further validated experimentally to serve as molecular target or biomarkers for anti-neoplastic therapy.

Combination immunotherapy with nivolumab and ipilimumab is an effective therapy in the treatment of metastatic melanoma, however, its benefit in older patients is unclear. A multicentre retrospective study was performed to compare the efficacy and toxicity of combination immunotherapy in metastatic melanoma in patients ≥65 years versus &lt;65 years, and complications of steroids used to manage toxicity. One hundred and thirty-nine patients were included with 52 patients ≥65 years (median age: 70; range: 65-83) and 87 patients &lt;65 years (median age: 52; range: 22-64). Median overall survival was similar in patients ≥65 years versus &lt;65 years (14.9 vs. 17.3 months p = .58). Median progression-free survival was also similar in both groups (7.1 vs. 6.9 months p = .79), as was overall response rate (48.1% vs. 44.8% p = .73). Age was not associated with a difference in overall survival on multivariate analysis. There was similar rates of Grade 3 or higher adverse events in patients ≥65 years versus &lt;65 years (50% vs. 49% p = 1.0) and discontinuation rates secondary to toxicity (55.8% vs. 56% p = 1.0). Median duration of steroids used to treat adverse events was similar (11 vs. 12 weeks p = .46). Complications of steroids requiring inpatient admission was numerically higher in the older patients (41.3% vs. 20.4% p = .07). Patients ≥65 years received similar benefit from combination immunotherapy in comparison to their younger counterparts with similar toxicity., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Parathyroid carcinoma is an uncommon cause of PTH-dependent hypercalcemia. Only a handful of cases have been reported of parathyroid carcinoma during pregnancy., Case Presentation: Twenty-four - Year - old female presented with proximal myopathy was found to have hypercalcemia. Her serum corrected total calcium was - 15 mg/dl (8.5 - 10.3), serum phosphate - 2.3 mg/dl (2.5 - 4.5), intact PTH - 118 pg/ml (20 - 80), Vitamin D - 15 ng/ml and Urine Ca/Cr ratio - 2.1 (0.1 - 0.2). Her CECT-neck revealed a well-defined mass lesion posterior to the right lobe of the thyroid - 2.6 cm × 2.5 cm × 2.9 cm in size. She was started on vitamin D supplementation, and she underwent right lower focal parathyroidectomy. Her PTH levels normalized following surgery. Her histology revealed an atypical parathyroid adenoma. She was treated with calcium and vitamin D. Her follow up was uneventful. One year following initial surgery the patient became pregnant and at 16 weeks of POA, the patient presented with a rapidly enhancing neck mass for one week duration. Her biochemical investigations were suggestive of a recurrence of primary hyperparathyroidism. Her ultrasound scan of the neck revealed a well-defined discreate hypoechoic nodule, superior to the thyroid isthmus which was confirmed by a non-contrast MRI scan of the neck. She underwent an uncomplicated second trimester parathyroid tumour excision with normalization of post op PTH. Her histology revealed a parathyroid carcinoma with vascular and capsular invasion. Her genetic studies revealed a novel frameshift mutation of the CDC73 gene. She was treated with calcium and vitamin D supplementation and closely followed up with ionized calcium and PTH levels which were normal throughout the pregnancy. She had an uncomplicated caesarean section at a POA of 37 weeks. Currently she is twelve weeks post-partum, in remission of disease., Conclusion: This case shows the importance of stringent follow up of atypical parathyroid adenoma patients, the benefit of second trimester surgery in management of hypercalcemia due to parathyroid carcinoma during pregnancy and the importance of identifying the novel CDC73 gene mutation., (© 2022. The Author(s).)

Met is an oncogene aberrantly activated in multiple cancers. Therefore, to better understand Met biology and its role in disease we applied the Ma mmalian M embrane T wo- H ybrid (MaMTH) to generate a targeted interactome map of its interactions with human SH2/PTB-domain-containing proteins. We identified thirty interaction partners, including sixteen that were previously unreported. Non-small cell lung cancer (NSCLC)-focused functional characterization of a Met-interacting protein, BLNK, revealed that BLNK is a positive regulator of Met signaling, and modulates localization, including ligand-dependent trafficking of Met in NSCLC cell lines. Furthermore, the interaction between Met and GRB2 is increased in the presence of BLNK, and the constitutive interaction between BLNK and GRB2 is increased in the presence of active Met. Tumor phenotypical assays uncovered roles for BLNK in anchorage-independent growth and chemotaxis of NSCLC cell lines. Cumulatively, this study provides a Met-interactome and delineates a role for BLNK in regulating Met biology in NSCLC context., Competing Interests: Authors declare no competing financial interests., (© 2022 The Authors.)

A 48-year-old patient with a history of diabetes mellitus, presented to a surgical ward with abdominal pain. She was found to have hypokalemia. Her younger sister had passed away due to sudden cardiac death at the age of 25 years. Further evaluation revealed an elevated trans-tubular potassium gradient suggestive of renal potassium loss, normal blood pressure, hypomagnesemia, hypocalciuria, and alkalosis. Moreover, there was evidence of secondary hyperaldosteronism. Genetic studies revealed two heterozygous mutations of the SLC12A3 gene, including a novel mutation which has not been reported before anywhere in the world. She was treated with intravenous potassium supplementation and was later converted to oral potassium and oral magnesium supplementation with spironolactone. Her potassium and magnesium levels normalized and glycaemic control also improved. Hypokalemia and hypomagnesemia found in Gitelman syndrome may be associated with insulin resistance and correction of electrolytes can lead to better glycaemic control., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Purpose: Vitamin D deficiency/insufficiency may increase the susceptibility to coronavirus disease 2019 (COVID-19). We aimed to determine the association between vitamin D deficiency/insufficiency and susceptibility to COVID-19, its severity, mortality, and role of vitamin D in its treatment., Methods: We searched CINAHL, Cochrane library, EMBASE, PubMED, Scopus, and Web of Science up to May 30, 2021, for observational studies on association between vitamin D deficiency/insufficiency and susceptibility to COVID-19, severe disease, and death among adults, and, randomized controlled trials (RCTs) comparing vitamin D treatment against standard care or placebo, in improving severity or mortality among adults with COVID-19. Risk of bias was assessed using Newcastle-Ottawa scale for observational studies and AUB-KQ1 Cochrane tool for RCTs. Study-level data were analyzed using RevMan 5.3 and R (v4.1.0). Heterogeneity was determined by I2 and sources were explored through prespecified sensitivity analyses, subgroup analyses, and meta-regressions., Results: Of 1877 search results, 76 studies satisfying eligibility criteria were included. Seventy-two observational studies were included in the meta-analysis (n = 1 976 099). Vitamin D deficiency/insufficiency increased the odds of developing COVID-19 (odds ratio [OR] 1.46; 95% CI, 1.28-1.65; P < 0.0001; I2 = 92%), severe disease (OR 1.90; 95% CI, 1.52-2.38; P < 0.0001; I2 = 81%), and death (OR 2.07; 95% CI, 1.28-3.35; P = 0.003; I2 = 73%). The 25-hydroxy vitamin D concentrations were lower in individuals with COVID-19 compared with controls (mean difference [MD] -3.85 ng/mL; 95% CI, -5.44 to -2.26; P ≤ 0.0001), in patients with severe COVID-19 compared with controls with nonsevere COVID-19 (MD -4.84 ng/mL; 95% CI, -7.32 to -2.35; P = 0.0001) and in nonsurvivors compared with survivors (MD -4.80 ng/mL; 95% CI, -7.89 to -1.71; P = 0.002). The association between vitamin D deficiency/insufficiency and death was insignificant when studies with high risk of bias or studies reporting unadjusted effect estimates were excluded. Risk of bias and heterogeneity were high across all analyses. Discrepancies in timing of vitamin D testing, definitions of severe COVID-19, and vitamin D deficiency/insufficiency partly explained the heterogeneity. Four RCTs were widely heterogeneous precluding meta-analysis., Conclusion: Multiple observational studies involving nearly 2 million adults suggest vitamin D deficiency/insufficiency increases susceptibility to COVID-19 and severe COVID-19, although with a high risk of bias and heterogeneity. Association with mortality was less robust. Heterogeneity in RCTs precluded their meta-analysis., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In recent years, the research community has, with comprehensive systems biology approaches and related technologies, gained insight into the vast complexity of numerous cancers. These approaches allow an in-depth exploration that cannot be achieved solely using conventional low-throughput methods, which do not closely mimic the natural cellular environment. In this review, we discuss recent integrative multiple omics approaches for understanding and modulating previously identified 'undruggable' targets such as members of the RAS family, MYC, TP53, and various E3 ligases and deubiquitinases. We describe how these technologies have revolutionized drug discovery by overcoming an array of biological and technological challenges and how, in the future, they will be pivotal in assessing cancer states in individual patients, allowing for the prediction and application of personalized disease treatments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

KRAS is one of the most frequently mutated oncogenes in human cancers. Despite nearly 40 years of research, KRAS remains largely undruggable, in part due to an incomplete understanding of its biology. Recently, KRAS dimerization was discovered to play an important role in its signalling function. The KRAS D154Q mutant was described as a dimer-deficient variant that can be used to study the effect of dimerization in KRAS oncogenicity. However, we show here that KRAS D154Q homo- and heterodimerized with KRAS WT using three separate protein-protein interaction assays, and that oncogenic KRAS dimerization was not negatively impacted by the presence of a secondary D154Q mutation. In conclusion, we advise caution in using this variant to study the purpose of dimerization in KRAS oncogenic behaviour., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Protein-protein interactions (PPIs) play essential roles in Anaplastic Lymphoma Kinase (ALK) signaling. Systematic characterization of ALK interactors helps elucidate novel ALK signaling mechanisms and may aid in the identification of novel therapeutics targeting related diseases. In this study, we used the Mammalian Membrane Two-Hybrid (MaMTH) system to map the phospho-dependent ALK interactome. By screening a library of 86 SH2 domain-containing full length proteins, 30 novel ALK interactors were identified. Many of their interactions are correlated to ALK phosphorylation activity: oncogenic ALK mutations potentiate the interactions and ALK inhibitors attenuate the interactions. Among the novel interactors, NCK2 was further verified in neuroblastoma cells using co-immunoprecipitation. Modulation of ALK activity by addition of inhibitors lead to concomitant changes in the tyrosine phosphorylation status of NCK2 in neuroblastoma cells, strongly supporting the functionality of the ALK/NCK2 interaction. Our study provides a resource list of potential novel ALK signaling components for further study., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Activating mutations in the epidermal growth factor receptor (EGFR) are common driver mutations in non-small cell lung cancer (NSCLC). First, second and third generation EGFR tyrosine kinase inhibitors (TKIs) are effective at inhibiting mutant EGFR NSCLC, however, acquired resistance is a major issue, leading to disease relapse. Here, we characterize a small molecule, EMI66, an analog of a small molecule which we previously identified to inhibit mutant EGFR signalling via a novel mechanism of action. We show that EMI66 attenuates receptor tyrosine kinase (RTK) expression and signalling and alters the electrophoretic mobility of Coatomer Protein Complex Beta 2 (COPB2) protein in mutant EGFR NSCLC cells. Moreover, we demonstrate that EMI66 can alter the subcellular localization of EGFR and COPB2 within the early secretory pathway. Furthermore, we find that COPB2 knockdown reduces the growth of mutant EGFR lung cancer cells, alters the post-translational processing of RTKs, and alters the endoplasmic reticulum (ER) stress response pathway. Lastly, we show that EMI66 treatment also alters the ER stress response pathway and inhibits the growth of mutant EGFR lung cancer cells and organoids. Our results demonstrate that targeting of COPB2 with EMI66 presents a viable approach to attenuate mutant EGFR signalling and growth in NSCLC., Competing Interests: Declaration of interests I.S., P.S. and J.S. (in conjunction with the University of Toronto) are listed as inventors on a patent (publication number 20190091205) for the use of EMI1 (and structurally related analogues), midostaurin, gilteritinib and AZD7762 (and structurally related analogues) in the treatment of mutant EGFR-mediated non-small-cell lung cancer., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Receptor tyrosine kinases (RTKs) are transmembrane receptors of great clinical interest due to their role in disease, notably cancer. Since their discovery, several mechanisms of RTK dysregulation have been identified, resulting in multiple cancer types displaying 'oncogenic addiction' to RTKs. As a result, RTKs have represented a major class for targeted therapeutics over the past two decades, with numerous small molecule-based tyrosine kinase inhibitor (TKI) therapeutics having been developed and clinically approved for several cancers. However, many of the current RTK inhibitor treatments eventually result in the rapid development of acquired resistance and subsequent tumor relapse. Recent technological advances and tools are being generated for the identification of novel RTK small molecule therapeutics. These newer technologies will be important for the identification of diverse types of RTK inhibitors, targeting both the receptors themselves as well as key cellular factors that play important roles in the RTK signaling cascade.

Receptor tyrosine kinases (RTKs) are transmembrane receptors of great clinical interest due to their role in disease. Historically, therapeutics targeting RTKs have been identified using in vitro kinase assays. Due to frequent development of drug resistance, however, there is a need to identify more diverse compounds that inhibit mutated but not wild-type RTKs. Here, we describe MaMTH-DS (mammalian membrane two-hybrid drug screening), a live-cell platform for high-throughput identification of small molecules targeting functional protein-protein interactions of RTKs. We applied MaMTH-DS to an oncogenic epidermal growth factor receptor (EGFR) mutant resistant to the latest generation of clinically approved tyrosine kinase inhibitors (TKIs). We identified four mutant-specific compounds, including two that would not have been detected by conventional in vitro kinase assays. One of these targets mutant EGFR via a new mechanism of action, distinct from classical TKI inhibition. Our results demonstrate how MaMTH-DS is a powerful complement to traditional drug screening approaches.

A 52-year-old male patient with hyaluronic acid-based dermal fillers injected in his cheeks was diagnosed with glossotonsillary malignancy, and managed with concurrent cetuximab (epidermal growth factor receptor inhibitor) and radiation therapy. He developed significant inflammation around the dermal filler sites after first cycle of cetuximab which improved with dissolution of the dermal fillers with hyaluronidase. This suggests that cetuximab can lead to inflammation around the dermal filler sites, which can be treated with dissolution of the filler., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Despite advances in medical therapies, disparity in outcome between rural and urban patients remain in Australia and many Western countries., Aims: To examine time delays in lung cancer referral pathways in North Queensland (NQ), Australia, and explore patients' perspective of factors causing these delays., Methods: Prospective study of patients attending three cancer centres in Townsville, Cairns and Mackay in NQ from 2009 to 2012. Times along referral pathway were divided as follows: Onset of symptoms to treatment (T1), symptoms to general practitioner (GP) (T2), GP to specialist (T3) and Specialist to treatment (T4). Quantitative and qualitative methods were used for analysis., Results: In total, 252 patients were participated. T1 was influenced by remoteness (125 days in Townsville vs 170 days for remote, P = 0.01), T2 by level of education (91 days for primary education vs 61 days for secondary vs 23 days for tertiary/Technical and Further Education (TAFE), P = 0.006), and age group (14 days for 31-50 years, 61 days for 51-70 years, 45 days for >71 years, P = 0.026), T3 by remoteness (15 days for Townville and 29.5 days for remote, P = 0.02) and T4 by stage of disease (21 days for Stage I, 11 days for Stage II, 34 days for Stage III 18 days for Stage IV, P = 0.041). Competing priorities of family and work and cost and inconvenience of travel were perceived as rural barriers., Conclusion: Remoteness, age and level of education were related to delays in various time lines in lung cancer referral pathways in NQ. Provision of specialist services closer to home may decrease delays by alleviating burden of cost and inconvenience of travel., (© 2018 Royal Australasian College of Physicians.)

Introduction: Maintaining the relative dose intensity (RDI) of adjuvant chemotherapy at ≥ 85% has been associated with improved treatment outcomes in early-stage breast cancer (ESBC). Increasing evidence has suggested that patients aged ≥ 65 years can maintain the optimal RDI for standard chemotherapy regimens. The present study investigated the RDI of newer adjuvant chemotherapy regimens in this demographic., Patients and Methods: We retrospectively analyzed the data from 281 patients aged ≥ 65 years with a diagnosis of ESBC who had received adjuvant chemotherapy across 3 sites in Queensland, Australia from 2010 to 2015. The primary endpoint was the proportion of patients who had received an RDI of ≥ 85%., Results: The median age at diagnosis was 68 years (range, 65-85 years), with 36.3% aged > 70 years. The patient characteristics included tumor stage T3 or T4 in 17% and node-positive disease in 60%. The common chemotherapy regimens included docetaxel/cyclophosphamide (23%), 5-fluorouracil/epirubicin/cyclophosphamide plus docetaxel or paclitaxel (17%); Adriamycin/cyclophosphamide/weekly paclitaxel (38%); and docetaxel/carboplatin/trastuzumab (11%). Primary (15%) and secondary (54%) granulocyte colony-stimulating factor (G-CSF) was used. An RDI of ≥ 85% was achieved in 63% of the patients. Significant associations were noted between a reduced RDI and age ≥ 70 years (P < .001), Charlson comorbidity index ≥ 1 (P = .043), initial dose reductions (P = .01), secondary G-CSF use (P = .45), hospital admission (P < .001), and febrile neutropenia (P = .007). Treatment-related toxicities were the most common reason for noncompletion, with high rates of hospital admissions (46%) and febrile neutropenia (22%)., Conclusion: Our findings suggest that patients aged ≥ 65 years with ESBC can maintain an optimal RDI with modern chemotherapy regimens. Appropriate geriatric assessment and the use of supportive measures such as G-CSF could better assist select groups to maintain an optimal dose intensity., (Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved.)

The Shrimad Bhagavad Gita enlightens everyone on how to cope up with various situations in life. It uses the conversation between Lord Krishna and Arjuna to highlight initial negative coping mechanisms exhibited by the latter. It goes on to showcase positive coping skills suggested by Lord Krishna and implemented by Arjuna. The Bhagavad Gita, through this "case-based methodology," teaches us how to cope with a demanding situation. Diabetes is a lifestyle disease, which warrants a thorough change in one's lifestyle, including changes in basic activities such as diet and exercise. This brief communication utilizes the teachings of Bhagavad Gita to help in coping with illness, especially chronic illness such as diabetes. The article cites verses from the Bhagavad Gita to show how one may cope with the stress of illness such as diabetes., Competing Interests: There are no conflicts of interest.

Concordance for schizophrenia is high in monozygotic twins but the extent to which concordance varies according to the presence of other schizophrenia risk factors is not well established. We aimed to investigate this in systematically ascertained twin samples. DSM-III-R/DSM-IV diagnoses were made from original data or published case histories from four systematically ascertained monozygotic twin samples. Probandwise concordance for schizophrenia was calculated according to the presence of psychotic disorder in first-degree relatives, birth order, gender, and age-at-onset. Logistic regression analysis was also performed to adjust for potential confounders. Psychotic disorder in parents and earlier age-at-onset were significantly associated with higher probandwise concordance for schizophrenia, including after adjustment for potential confounders. For example, when no parents had a psychotic disorder concordance was 34/88 (38.6%) versus 10/16 (62.5%) when one parent was affected; and for age-at-onset <23 years concordance was 25/46 (54.3%), declining to 13/44 (29.5%) for age-at-onset >30 years. These results are consistent with psychotic disorder in parents and age-at-onset being markers of the level of familial liability to schizophrenia and these factors may be useful in genetic counseling of monozygotic twins and in identifying and managing those at particularly high risk, if these findings are further replicated., (© 2018 Wiley Periodicals, Inc.)

Competing Interests: Competing interests: None declared.

Competing Interests: Competing interests: None declared

Non-typhi Salmonella enterica infection rarely presents as a pleural empyema, with only 31 cases published in the literature over the last century. We report a case of an 85-year-old female with worsening shortness of breath and pleuritic chest pain, and a chest radiograph showing a right-sided pleural effusion. Thoracocentesis revealed Salmonella enterica serovar Typhimurium to be the causative organism. This was on a background of recurrent pleural effusion secondary to congestive heart failure, with thoracocentesis one month previously showing a transudative picture. This case highlights the possibility of S. enterica as a differential diagnosis in the management of pleural effusions., (© The Author(s) 2015.)

A practical, multi-gram 10-step synthesis of racemic herbindole A, B, and C from a common intermediate is described. The key step features a remarkably regioselective C-7 metal-halogen exchange and elimination from a Bartoli-generated N - t -butyldimethylsilyl-4,6,7-tribromo-5-methylindole scaffold to afford the 6,7-indole aryne. Cycloaddition with cyclopentadiene, oxidative cleavage, and Fujimoto reduction gave a common intermediate from which all three herbindoles were readily derived. A final Pd(0)-catalyzed Negishi and Stille cross-coupling reaction at the C-4 bromide afforded each of the herbindoles on a multigram scale.

Diaphragmatic hernias that are diagnosed in adulthood may be traumatic or congenital in nature. Therefore, respiratory specialists need to be aware of the presentation of patients with these conditions. In this report, we describe a case series of patients with congenital and traumatic diaphragmatic hernias and highlight a varied range of their presentations. Abnormalities were noted in the thorax on the chest radiographs, but it was unclear as to the nature of the anomaly. The findings on thoracic ultrasound conducted by a pulmonologist helped to direct appropriate investigations avoiding unnecessary interventions. Instead of pleural effusions, consolidation or collapse, thoracic computed tomography demonstrated diaphragmatic hernias which were managed either conservatively or by surgery. There is increasing evidence that pulmonary specialists should be trained in thoracic ultrasonography to identify pleural pathology as well as safely conducting pleural-based interventions.

The aim of the study was to compare the compositions of the fecal microbiotas of infants fed goat milk formula to those of infants fed cow milk formula or breast milk as the gold standard. Pyrosequencing of 16S rRNA gene sequences was used in the analysis of the microbiotas in stool samples collected from 90 Australian babies (30 in each group) at 2 months of age. Beta-diversity analysis of total microbiota sequences and Lachnospiraceae sequences revealed that they were more similar in breast milk/goat milk comparisons than in breast milk/cow milk comparisons. The Lachnospiraceae were mostly restricted to a single species (Ruminococcus gnavus) in breast milk-fed and goat milk-fed babies compared to a more diverse collection in cow milk-fed babies. Bifidobacteriaceae were abundant in the microbiotas of infants in all three groups. Bifidobacterium longum, Bifidobacterium breve, and Bifidobacterium bifidum were the most commonly detected bifidobacterial species. A semiquantitative PCR method was devised to differentiate between B. longum subsp. longum and B. longum subsp. infantis and was used to test stool samples. B. longum subsp. infantis was seldom present in stools, even of breast milk-fed babies. The presence of B. bifidum in the stools of breast milk-fed infants at abundances greater than 10% of the total microbiota was associated with the highest total abundances of Bifidobacteriaceae. When Bifidobacteriaceae abundance was low, Lachnospiraceae abundances were greater. New information about the composition of the fecal microbiota when goat milk formula is used in infant nutrition was thus obtained.

Regadenoson (REG) is a A2a receptor selective pharmacologic SPECT imaging agent. Its safety in unselected chronic obstructive pulmonary disease (COPD) or asthma (AM) undergoing SPECT imaging has not been well evaluated. We retrospectively identified 228 patients (COPD n = 126 and AM n = 102, Grp 1) undergoing REG SPECT from Jan to Nov 2009 and compared to 1,142 patients without COPD and AM (control, Grp 2). A standard 400 μg REG bolus was used and gated Tc-99 m tetrofosmin SPECT done. Patient demographics, REG SPECT data, side effects, arrhythmia occurrences, and any exacerbation of COPD or AM leading to treatment, hospitalization or death were evaluated. The side effect profile of Grp 1 was also compared to a historical cohort who underwent intravenous dipyridamole thallium-201 imaging and adenosine SPECT. Both groups were comparable with regards to baseline characteristics. There was 0% incidence of clinical exacerbation of COPD or AM after REG. COPD patients had more non-significant arrhythmias (58.3% vs. Grp 2, 43%, P = 0.004). There was 0% incidence of any atrio-ventricular block and only 2 instances of brief supraventricular tachycardia. When compared to the historical cohort of COPD who underwent IV dipyridamole thallium imaging, COPD in Grp 1, had more dyspnea and flushing and when compared to COPD/AM patients who underwent adenosine SPECT, Grp 1 pts had more of flushing and headache (24.9% vs. 2.8%, P = <0.001) but less of bronchospasm (1.3% vs. 6.9%, P = 0.022) and AV block (0% vs. 4.2%, P = 0.014). REG SPECT can be safely performed in COPD and AM population.

Chronic cough is a common symptom carrying significant morbidity which can occur as a result of oesophageal dysmotility. Here we report 2 patients with musculoskeletal disease presenting with chronic cough to our tertiary cough clinic. Prior to referral both patients had been extensively investigated to determine the basis of their cough, with no cause found. Oesophageal studies, using high resolution oesophageal manometry, demonstrated oesophageal dysmotility with consequent airway reflux. Anti-reflux therapy resulted in a good response in both patients. These are the first reports of the recently developed technique of high resolution manometry aiding the diagnosis of chronic cough. This technique may provide important clues into aetiological mechanism in patients with conditions predisposing to reflux into the airways.

The IQGAP [IQ-motif-containing GAP (GTPase-activating protein)] family members are eukaryotic proteins that act at the interface between cellular signalling and the cytoskeleton. As such they collect numerous inputs from a variety of signalling pathways. A key binding partner is the calcium-sensing protein CaM (calmodulin). This protein binds mainly through a series of IQ-motifs which are located towards the middle of the primary sequence of the IQGAPs. In some IQGAPs, these motifs also provide binding sites for CaM-like proteins such as myosin essential light chain and S100B. Using synthetic peptides and native gel electrophoresis, the binding properties of the IQ-motifs from human IQGAP2 and IQGAP3 have been mapped. The second and third IQ-motifs in IQGAP2 and all four of the IQ-motifs of IQGAP3 interacted with CaM in the presence of calcium ions. However, there were differences in the type of interaction: while some IQ-motifs were able to form complexes with CaM which were stable under the conditions of the experiment, others formed more transient interactions. The first IQ-motifs from IQGAP2 and IQGAP3 formed transient interactions with CaM in the absence of calcium and the first motif from IQGAP3 formed a transient interaction with the myosin essential light chain Mlc1sa. None of these IQ-motifs interacted with S100B. Molecular modelling suggested that all of the IQ-motifs, except the first one from IQGAP2 formed α-helices in solution. These results extend our knowledge of the selectivity of IQ-motifs for CaM and related proteins.