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Background : Polycystic ovary syndrome is one of the emerging endocrinological condition among women of reproductive age . PCOS affect their mental health as well. There are many researches going on PCOS. Aim of the study : This study was done with an aim to see the prevalence of psychiatry comorbidities among PCOS patients attending Gynaecology department as well as Psychiatry department of Guwahati medical college and hospital, a tertiary care centre in North eastern area of the country. Methodology: This was a hospital based cross sectional observational study done over a period of one year, from April 2021 to May 2022 . Sample size was 50. Method of sampling was convenient sampling. Patients attending Gynaecology out patient department and Psychiatry department of Gauhati medical college and hospital diagnosed as a case of PCOS by treating physician were enrolled in the study after getting informed written consent. Psychiatric diagnosis was given based on ICD 10 classication of mental and behavioural disorder. The study shows that prevalence of Result : psychiatric disorders in PCOS patients were found to be 48% among which mood disorder were more than anxiety disorder. PCOS Conclusion : patients are vulnerable for development of psychiatric problems, so they should always be assessed for psychiatric comorbidities .By knowing the trend of psychiatric illnesses among the patients in a particular geographic area paves the way for future consideration in their management.

Introduction: Obstructive jaundice is frequently encountered worldwide including Bangladesh. Therapeutic Endoscopic Retrograde Cholangiopancreatography (ERCP) is one of the procedures to manage obstructive jaundice. Objectives: To ascertain the outcome of obstructive jaundice patients who underwent ERCP. Materials and Methods: It was a hospital based cross sectional observational study, carried out in Gastroenterology Department of Combined Military Hospital (CMH) Dhaka from May 2017 to May 2019. Total 200 patients were included in the study. Verbal consents were taken from patients. Data were collected with a checklist and analyzed by using SPSS 20. Results: Total 200 patients’ mean age±SD was 56.5±14.5 years with range 21 to 92 years and majority were 41 to 60 years 80(40%) followed by 61 to 80 years 78(39%). Etiology of obstructive jaundice were, benign 137(68.5%) and malignant 63(31.5%). Among the benign: 69(34.5%) were choledocholithiasis, 45(22.5%) biliary stricture, 20(10.0%) papillary stenosis and 3(1.5%) biliary warms. Among the malignant: 24(12.0%) were distal cholangiocarcinoma, 21(10.5%) periampullary tumors, 10(5.0%) Klatskin tumor, 4(2.0%) carcinoma head of pancreas, and 4(2.0%) other malignancy. Mean serum bilirubin level 17.6 mg/dl with minimum 0.6mg/dl, maximum 41.3mg/dl; mean alkaline phosphatase (ALP) level 351.4U/L with minimum 111U/L and maximum 1262U/L; mean alanine aminotransferase (ALT) level 118.8 U/L with minimum 28 U/L, maximum 521 U/L; ERCP were successfully done in 188(94.0%) patients with single attempt 171 (85.5%), repeated sessions 17(8.5%) and 12(6.0%) patients unsuccessful ERCP; complications occurred in 17(8.5%)patients, of whom post-ERCP pancreatitis 9(4.5%) and post procedure cholangitis 4(2.0%)patients. Conclusion: Benign etiologies of obstructive jaundice were more common than malignant one. Both benign and malignant etiology of obstructive jaundice can be successfully managed with ERCP with few complications. JAFMC Bangladesh. Vol 16, No 2 (December) 2020: 27-30

Introduction: Diverse manifestation of recent dengue outbreak has posed a challenge to pre-existing nature of dengue virus infection and management. This study was designed to observe clinicopathological profile and analyze the diverse presentation and outcome of dengue syndrome in recent outbreak in Bangladesh. Methods: This was a hospital based observational study, carried out in Medicine department of Combined Military Hospital (CMH) Dhaka cantonment in between May and September 2019. Total 300 laboratory-confirmed dengue cases aged more than 11 years presenting within 7 days of symptom onset were studied. Patients who presented 7 days after the onset of symptoms or those who were transferred to other hospitals were excluded from study. Results: Total patients were 300 with male predominance (187, 62.3%) and mean age±SD was 37.6±7.5years with age range 12 to76 years; common presentations were fever (300, 100%),headache (265, 88.3%), skin rash (197, 65.7%), bodyache (186, 62.0%),vomiting (152, 50.7%), diarrhoea (65, 21.7%),abdominal pain (58, 19.3%), and bleeding manifestation (36, 12.0). Eighty four (28%) patient had classical dengue fever (DF), 61 (20.3%) had dengue haemorrhagic fever (DHF), 45(15%) had dengue shock syndrome (DSS) and 110(36.7%) had expanded dengue syndrome(EDS). Relevant investigations showed 157(52.3%) patients had leukopenia,18(6%) had leukocytosis, 254(84.7%) had thrombocytopenia with lowest platelet count 1x109/L,135(45%) had abnormal ALT, 110(36.7%) had abnormal AST, 84(28%) had hyponatraemia,43(14.3%) had AKI,125(41.7%) had pleural effusion with 36(12%) bilateral;102(34%) had ascites, 25(8.3%) developed acalculous cholecystitis;7(2.3%) patient developed cerebrovascular accident. Eighteen (6%) patients required mechanical ventilation and 15 (5%) patients required haemodialysis. Regarding outcome, 5 (1.7%) patients died and 295 (98.3%) patients survived. Conclusion: Dengue fever was presented with common as well as other features and involved a number of organs including liver, kidneys, brain, pleura, peritoneum, and gall bladder and had diverse manifestations and adverse outcome. J Bangladesh Coll Phys Surg 2021; 39: 213-219

Key to realizing practical resonators for liquid-phase sensing applications is efficient electromechanical transduction and reasonable ${Q}$ in liquid, which determine the motional resistance ( ${R}_{m}$ ). Both lower ${R}_{m}$ and high liquid phase ${Q}$ are important for realizing a more stable close-loop oscillator to allow a lower detection limit. But ${R}_{m}$ usually increases when scaling down resonator size, leading to weak output signals in liquid. This article describes a piezoelectrically transduced micromechanical elliptical plate resonator (EPR) targeting liquid-phase sensing applications. The proposed EPR delivers lower ${R}_{m}$ relative to other disk-based modes and has a reasonable ${Q}$ in water. These two features are critical for eventually realizing a closed-loop system to enable real-time frequency tracking for sensing applications. The low ${R}_{m}$ arises from enhanced transduction efficiency associated with the modal lateral strain profile. The EPR’s moderate liquid phase ${Q}$ stems from transducing a stiff lateral bulk mode that increases energy storage. The proposed EPR can be scaled down more efficiently compared to other disk-based modes in the limit of mode shape distortion by anchors when scaling down the resonator below a threshold. Experimental results in water are demonstrated for a $500~\mu \text{m}$ by $400~\mu \text{m}$ EPR, which delivers an ${R}_{m}$ of only 2.68 $\text{k}{\Omega }$ in water without feedthrough cancellation. Scaling down the device to $300~\mu \text{m}$ by $200~\mu \text{m}$ , we demonstrate an ${R}_{m}$ of just 5.5 $\text{k}\Omega $ and ${Q}$ of 245 in water. The proposed EPR topology boasts the lowest ${R}_{m}$ among resonators immersed in liquid after normalizing over the device area.

Introduction: Vitamin D deficiency or insufficiency is a worldwide problem including Bangladesh. It is common in Rheumatological diseases. Objectives: To find outthe clinical correlation of serum Vitamin D level with Rheumatological diseases. Materials and Methods: This was a hospital based case control study. It was conducted in Rheumatology department of Combined Military Hospital Dhaka. Total 100 patients having Rheumatological diseases and 100 age and sex matched healthy control were included in the study. Data were collected from face to face interview, clinical examination and relevant investigation reports and processed with SPSS version 20 and obtained in tables and charts. Results: Among 100 study patients’Osteoarthritis (OA) were 24(24.0%), Rheumatoid arthritis (RA) 20(20.0%), SLE 16(16.0%), Osteoporosis 16(16.0%), Ankylosing spondylitis (AS) 10(10.0%), Chikungunya arthritis (CS) 4(4.0%)and other arthritis 10(10.0%). Among patients group 84(84.0%) had vitamin D deficiency/ insufficiency, of whom OA were 20(23.80%), RA 16(19.04%), SLE 16(19.04%), osteoporosis 14 (16.66%),AS 8(9.52%), CS 2(2.38%) and other arthritis 8(9.52%).Abnormal vitamin D level were in SLE 16(100.0%), osteoporosis 14(87.50%), OA20(83.33%), RA(80.0%), AS 8(80.0%), CS 2(50.0%), and other arthritis 8(80.0%).In study patients, 60 had adequate sun exposure of whom 48(72.07%) had low serum vitamin D level and 40 had inadequate sun exposure of whom 36 (90.0%) had low vitamin D level that reflects sunlight exposure affects vitamin D status.Abnormal serum vitamin D level was more common in Rheumatological diseased patients than healthy group (p

[Image: see text] A combination of focused library and virtual screening, hit expansion, and rational design has resulted in the development of a series of inhibitors of RET(V804M) kinase, the anticipated drug-resistant mutant of RET kinase. These agents do not inhibit the wild type (wt) isoforms of RET or KDR and therefore offer a potential adjunct to RET inhibitors currently undergoing clinical evaluation.

Background: Acute pancreatitis is an important cause of morbidity and mortality among gastrointestinal disorders. But little is known about etiology and clinical profile in Indian population. Objective: To know clinicopathological profile, etiology and outcome of acute pancreatitis in study patients. Material and methods: This observational cross-sectional study was conducted in a tertiary care and research hospital in New Delhi India from May 2018 to November 2018. Total 30 established cases of acute pancreatitis were included in the study. Data were collected and processed by using SPSS version20 and result was obtained in tables and diagrams. Results: Among 30 patients, 21(70%) were male and 9(30%) female; 18 to 89 yrs of aged patients were included in the study with mean age 41.6±17.5 years, of 18-30 years of aged patients were more affected (10, 33.3%); patients of different occupation were studied;26(86.7%)patients were non-smoker and 4(13.3%) smoker; 16(53.3%) were non-alcoholic and 14(46.7%) patients had a habit of alcoholism of whom, all were male; patients who used to take e”5 units of alcohol per day were frequently affected (10, 71.4%) by acute pancreatitis, though it did not spared occasional drinkers (2, 14.3%);22(73.3%) patients had interstitial pancreatitis and 8(26.7%) had acute necrotizing pancreatitis;14(46.7%) patients had acute pancreatitis due to alcohol, 10 (33.3%) patients had gall stone, 2(6.7%) patients developed pancreatitis after ERCP;29(96.7%) patients presented with abdominal pain, 28 (93.3%) had vomiting, 21 (70%) patients had jaundice, 10 (33.3%) had fever, 18 (60%) patients had anemia, 17 (56.7%) patients develop ascites, 19 (63.3%) patients develop pleural effusion, 7(23.3%) patients developed ileus, and 3(10.0%) patients developed circulatory shock; 25(83.3%) patients developed organ dysfunction during in hospital care, of whom 11(36.7%) patients had transient and 14(46.7%) had persistent organ dysfunction; 5(16.7%) patients were complicated with pseudocyst, 6(20%) had walled of necrosis (WON), 7(23.3%) developed sepsis, 14(46.7%) developed renal dysfunction, 23(76.7%) developed hepatic dysfunction, 8(26.7%) developed respiratory dysfunction, 6(20%) developed pneumonia; 8(26.7%) patients had been suffering from different comorbidity; ultrasound of abdomen were abnormal in all 30(100%) patients; As per CTSI score, severe pancreatitis 14(46.7%), moderate pancreatitis 14(46.7%) and mild pancreatitis 2(6.7%); 24(80%) patients received only medical treatment and 6(20%) patients needed surgical or radiological intervention; 19(63.3%) patients were improved symptomatically, 8(26.7%) patients were cured and 3(10%) patients died during in hospital care. Conclusion: Alcohol was the predominant etiology of acute pancreatitis, mostly affecting young and middle aged male, but mortality was more in gall stone related pancreatitis. Hepatic dysfunction was observed frequently that may attribute to effect of chronic alcohol abuse. J Bangladesh Coll Phys Surg 2020; 38(2): 86-92

The ability to weigh microsubstances present in low concentrations is an important tool for environmental monitoring and chemical analysis. For instance, developing a rapid analysis platform that identifies the material type of microplastics in seawater would help evaluate the potential toxicity to marine organisms. In this study, we demonstrate the integration of two different techniques that bring together the functions of sparse particle localization and miniaturized mass sensing on a microelectromechanical system (MEMS) chip for enhanced detection and minimization of negative measurements. The droplet sample for analysis is loaded onto the MEMS chip containing a resonant mass sensor. Through the coupling of a surface acoustic wave (SAW) from a SAW transducer into the chip, the initially dispersed microparticles in the droplet are localized over the detection area of the MEMS sensor, which is only 200 µm wide. The accreted mass of the particles is then calibrated against the resulting shift in resonant frequency of the sensor. The SAW device and MEMS chip are detachable after use, allowing the reuse of the SAW device part of the setup instead of the disposal of both parts. Our platform maintains the strengths of noncontact and label-free dual-chip acoustofluidic devices, demonstrating for the first time an integrated microparticle manipulation and real-time mass measurement platform useful for the analysis of sparse microsubstances.

Pernicious anaemia often poses diagnostic and therapeutic challenges to the clinician. Herein, we representing a 55 years old lady who presented with anaemia along with its classical symptoms and features of peripheral neuropathy due to Pernicious anaemia associated with Psoriasis and Arthropathy without any association of other autoimmune disorder. She had all objective evidences of autoimmune atrophic gastritis in gastric fundic biopsy and positive anti-intrinsic factor antibody. Treatment with injection vitamin B12 improved the condition rapidly. JAFMC Bangladesh. Vol 15, No 2 (December) 2019: 243-245

Vitamin D Deficiency is a world-wide problem and it is defined as 25(OH)D3 level below 20 ng/ml. It contributes skeletal and non-skeletal health effects. Musculo-skeletal abnormalities along with non-skeletal health effects such as microbial infection, cardiovascular disorders, cancers, autoimmune diseases, asthma and allergy, endocrine and metabolic diseases, mental health etc are seen in Vitamin D deficiency. Vitamin D deficiency or insufficiency is mostly under diagnosed or under attention topics or unaware matter to general population. It is mostly preventable and treatable condition that needs due attention to life-style modification, medication, self-awareness and campaign and further research. Journal of Armed Forces Medical College Bangladesh Vol.14(1) 2018: 78-83

Acoustofluidic platforms typically enable only rectangular matrix-like of particle patterns in a closed microchamber actuated by a surface acoustic wave (SAW) device. More complex and unique patterns require a sophisticated and dedicated SAW transducer. As a first, we demonstrate the generation of ring-shape particle patterns on-chip actuated by a simple generic SAW transducer. The ability to reshape unique acoustic field on-chip is realized by using a bulk micromachined microelectromechanical systems (MEMS) chip. We also show for the first time the creation of a two-dimensional (2D) pattern with just a one-dimensional (1D) standing SAW (SSAW). These results pave the way toward truly plug-and-play acoustofluidics, where unique patterns are defined by a diverse range of interchangeable chips on a standard SAW transducer.

Phononic crystals (PnC) can help shape acoustic fields to enhance microfluidic functions in acoustofluidic devices. But operating within the defined phononic band gap (PBG) limits the scope for optimizing microfluidic functions. We show, for the first-time, efficient droplet centrifugation that works outside the range of the PBG. Instead of using deep reactive ion etching (DRIE) to create the PnC, we here use laser machining with the aim to demonstrate low cost and rapid prototyping of complex superstrates that can enhance particle concentration greatly. The results of this work are significant given that the center frequency of a PBG is tied to the size of the PnC. In the case of particle concentration, the efficiency increases with frequency. As such, working in the confines of a PBG requires a high level of precision in fabrication. The ability to work outside PBGs removes such restrictions, opening a range of possibilities. Besides, the results are based on a two-chip approach that yields a low-cost solution for disposable single-use acoustofluidics.

Acetylation of histones and additional nuclear proteins is a key mechanism in the regulation of gene expression. Aberrant acetylation has been linked to a wide range of diseases including cancer, inflammation, and neurodevelopmental disorders. Histone acetylation is introduced by histone acetyltransferases complexes (HATs), where substrate specificity is dramatically enhanced by scaffolding proteins that activate and target them to specific chromatin sites. A protein of interest with both epigenetic acetyl reader and scaffolding function is the protein Bromodomain and PHD finger-containing protein 1 (BRPF1). The Protein contains domains of two plant homeodomain (PHD) fingers separated by a zinc knuckle (PZP domain), a bromodomain, and a proline-tryptophan-tryptophan-proline (PWWP) Tudor domain. Native BRPF1 complexes can contain either MOZ/MORF or HBO1 as the catalytic MYST-family acetyltransferase subunit and the stable complex with Moz-Tif2 is known to lead to the development of human acute myeloid leukemia (AML). Given this, we chose to pursue the development of BRPF1 degraders to probe cancer disease biology especially in AML, where new therapies are required to overcome several unmet needs such as less-toxic treatments and relapsed/refractory disease paradigms. Here we present the design and synthesis of a range of BRPF1 degraders in highly desirable physicochemical space utilizing in-silico modeling. The prepared degraders which utilize multiple E3 ligases were then screened against cell lines harboring Mixed-lineage leukemia (MLL) translocations specifically the THP-1 cell line. In addition to this, we investigated the ability of the compounds to effectively degrade the target and suitability of our degraders for potential in-vivo exposure through a panel of routine ADMET assays. Citation Format: Daniel Joseph Glynn, Rosie Crampton, Thomas Pesnot, Andrew Scott, Anne-Chloe Nassoy, Ralph Kirk, Daniele Narducci, Gary Nelson, Lynette Ongiri, Habiba Begum, Vincent Rao, Matilda Bingham, Rhoanne McPherson, Darryl Turner. The development of BRPF1 degraders as a potential treatment for acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 419.

This paper reports the first demonstration of acoustic tweezers to manipulate microparticles in a sessile droplet over a functional surface-micromachined silicon chip fabricated with polysilicon micromechanical sensing structures. The proposed plug-and-play setup comprises two interchangeable parts: a detachable silicon micromachined sensor chip (acting as a superstrate) and a surface acoustic wave (SAW) device substrate. The SAW device provides the off-chip acoustic source from which Rayleigh waves couple into the functional silicon chip. We demonstrate concentration of initially randomly dispersed microparticles in a water droplet loaded on the functional silicon chip by means of acoustic streaming forces using a drive power of 1 W.

Dandy–Walker malformation (DWM) is a group of congenital human brain malformation with specific characteristics. It may be associated with a number of other organ malformation including heart, eye, and thyroid glands. In our case, DWM was associated with heart malformation in the form of patent ductus arteriosus (PDA) and was complicated by atrial fibrillation. The case was established by computed tomography of brain, echocardiography and electrocardiography. The patient was asymptomatic until 7 years of age.J Bangladesh Coll Phys Surg 2018; 36(3): 128-131

Childhood type 2 Diabetes Mellitus (DM) has increasingly been reported worldwide. It is commonly associated with childhood obesity.It may be presented with classical manifestation of DM such as polyuria, polydipsia, weight lossor acute complications like Diabetic ketoacidosis (DKA), Hyperglycemic Hyperosmolar State (HHS) or features of insulin resistance syndrome. Many a cases it may remain asymptomatic and hence undiagnosed.So,overweight children and adolescents who met screening criteria such as family history of type 2 DM, signs of insulin resistance, and high risk ethnics should undergo screening. Emphasis should be given on early diagnosis and optimum management plan to avoid grave consequences of it in early part of life. Diagnosis of type 2 Diabetes Mellitus in children should be done on the basis of standard diagnostic criteria such as American Diabetic Association (ADA) criteria. Both non-pharmacological and drug management are important equally. Multidisciplinary team approach including self-management plan is mandatory for obtaining optimal therapeutic goals of type 2 DM in children and adolescents. Lifestyle modification, dietary intervention, weight reduction, patient education, psychological support, and oral anti diabetic drugs and insulin therapy should be included in comprehensive diabetic management plan. Complications of type 2 DM should be minimized by all means with strict glycemic control and management of co-morbidity if any. Emphasis should also be given on prevention of type 2 DM by adopting a healthy lifestyle characterized by healthy eating behavior, regular physical activity and subsequent modest weight loss that can prevent the progression of impaired glucose tolerance to clinical diabetes mellitus.J Bangladesh Coll Phys Surg 2017; 35(1): 24-30

We present, for the first time, mass sensitivity measurements of a novel resonant mode based on a disk resonator that delivers the one of the highest Q-factors among resonators tested in liquid (Q of 362). The mode of interest is referred to as the Button-like (BL) mode as its associated lateral strain profile resembles a shirt button. In the context of mass sensing, the high Q-factor of the BL mode enhances mass resolution. Its motional resistance (R m ) in water is 5.3kΩ, which greatly eases the difficulty in designing control circuits. In this paper, we measured the mass sensitivity of the device by depositing chrome (Cr) on the bottom surface of the device through a back cavity. The resonator has a measured mass sensitivity of 17.2ppm/ng for uniformly deposited mass on the resonator’s surface.

Previous works have demonstrated the use of acoustic waves to manipulate microparticles and biological samples on bare glass and silicon superstrates. Traditionally, the surface acoustic wave (SAW) is converted into a Lamb wave propagating within a bare silicon superstrate via a thin coupling agent. The potential impact of acoustically driven microfluidics could be further augmented if applied to superstrates integrated with sensing structures that would allow sequential analysis after sample treatment. In this work, we demonstrate the applicability of acoustically-driven micro-centrifugation on a superstrate with multiple thin film layers to mimic sensing structures on a chip, and characterize the underlying performance. We propose an integrated plug-and-play platform comprised of a reusable SAW device interfaced to a disposable surface-micromachined silicon (SMS) superstrate processed with five layers of thin films. To address the shortcomings of existing coupling agents, we examine and compare the transmission efficiency and long-term stability of four kinds of coupling agents with the aim to enable disposable acoustofluidics applications. To investigate the effect of different superstrates on the performance of droplet centrifugation, we characterize and compare centrifugation on different superstrates. High-performance concentration was realized on the SMS superstrate under different conditions, such as input power, temperature, droplet volume, and particle size and density. In terms of more advanced fluidic handling functionality on a multi-layered SMS superstrate, we demonstrate ultrasonic isopycnic separation between microbeads differentiated by density on the SMS superstrate. The results herein lay the groundwork for realizing particle concentration on complex superstrates processed with multilayer films that represent a range of microfabricated sensors towards a broader goal of integrating acoustically driven concentration capabilities and sensing for applications in diagnostics and fundamental analysis.

Background: Breastfeeding reduces incidence of common childhood illnesses such as diarrhea and thus reduces infant mortality and morbidity.Objective: To find out the incidence of diarrhea in breastfed versus formula fed baby. Methodology: An observational cross sectional study was carried out in the Pediatric department of Northern private medical college hospital, Rangpur from March 2013 to June 2014. Total 150 children aged 1 to 24 months having diarrhea were enrolled in the study.Result: Mean age of children was 11.6 with SD ±5.29 months, ranges from 1 month to 23 months in which exclusively breast fed 51.3%, breast fed plus formula fed 39.3%, exclusively formula fed 9.4%; single attack of diarrhea occurred in 72.7%, 40.7%, and 28.6% children in exclusively breast fed, breast fed plus formula fed and exclusively formula fed children respectively. Frequent attack of diarrhea occurred in 27.3%, 59.3% and 71.4% children in exclusively breast fed, breast fed plus formula fed and exclusively formula fed children respectively; among 59 patients who developed first attack of diarrhea by 6 months of age, 10.2%, 69.5 % and 20.3% were from exclusively breast fed, breast fed plus formula fed and exclusively formula fed children respectively. Patients who developed first attack of diarrhea by 7-12 months of age, 69.8% were from exclusively breast fed, 27.0% from breast fed plus formula fed and 3.2% from exclusively formula fed children. But 28 children whose first diarrhea occurred by 13-24 months of age, 96.4% and 3.6% were from exclusively breast fed, and breast fed plus formula fed group respectively.Conclusion: Breast feeding reduces incidence of diarrhea, prevents frequent attack and early occurrence of diarrhea in under two children.J Bangladesh Coll Phys Surg 2016; 34(1): 21-25

Marshall Syndrome PFAPA (Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis) Syndrome is a chronic condition, typically starting 2-5 years old, in which fever occurs periodically (lasts for 3-7 days), accompanied by aphthous-like ulcers, pharyngitis and/or cervical adenitis. The patients have no clinical symptoms between episodes and it is required to exclude all other diseases before confirming the diagnosis. The dramatic response to treatment with steroid helps diagnosing PFAPA. We are presenting the case of an 8 years male patient, with the history of recurrent episodes of fever (onset at the age of two), oral ulcer and difficulty in deglutition who constantly received antibiotic therapy and or antifungal prescribed by different doctors. Clinically the patient was febrile, mildly pale, cervical lymphadenopathy, aphthous ulcers in the tongue with inflamed tonsils, covered with thick exudates and pharyngeal wall was inflamed and folliculated. There was just palpable liver. Laboratory investigations performed but it was without serological confirmation. Throat swab culture was negative. The child received steroid (Prednisolone) with favorable outcome. Subsequently, the patient presented with similar episodes of fever which disappeared within 24 hours of single dose of prednisolone. After Ranitidine (H2 blocker) prophylaxis the patient remains asymptomatic for about one and half years. With our best knowledge this is the first case report of Marshall Syndrome or PFAPA Syndrome in Bangladesh.J Bangladesh Coll Phys Surg 2016; 34(4): 222-224

Objectives: To describe the clinical profile as well as histopathological sub-types of Rhabdomyosarcoma in children.Methods: A hospital base prospective observational study was conducted among 20 diagnosed cases of Rhabdomyosarcoma in children, those attending in Hemato-Oncology department of Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka in the period between January to December 2009.Results: The peak incidence of Rhabdomyosarcoma was in 1-5 years of age group (n=9, 45%) with mean age 6.83 years with male to female ratio 5.66:1. The common sites of primary tumor was in head and neck region (40%, n=08), followed by genito-urinary tract, 30% (n=06), extremities 20% (n=04), trunk 10% (n=02). The most common clinical presentation was mass lesion 100% (n=20), followed by local pain 25% (n=05), urinary obstructions 15% (n=03) dysphagia, chronic otorrhea, dysuria, haematuria, and proptoses were 10% each (n=02, each); The histological sub-types were Embryonal 60% (n=12), alveolar 30% (n=6), and Botryoid 10% (n=02); Of Embryonal variety in head and neck region 58.33% (n=7), and Genito-urinary sites 41.67% (n=5); of Alveolar variety in trunk 66.67% (n=4), and in extremities33.33% (n=2), of Botryoid sub-type frequency was equal in head - neck region and genitourinary site 50% each (n=1).Conclusion: Children with Rhabdomyosarcoma presented mostly in 1 to 5 years of age, with mass lesion (100%), predominantly in head and neck region (40%) and the commonest histological sub-type was Embryonal variety (60%). DOI: http://dx.doi.org/10.3329/jbcps.v30i3.12461 J Bangladesh Coll Phys Surg 2012; 30: 132-136

Poly(ADP-ribose) glycohydrolase (PARG) hydrolyzes poly(ADP-ribose) (PAR) chains that are polymerized by PARP enzymes, completing the PAR cycle. Small molecule inhibitors of PARG result in a dose dependent increase in cellular PAR after DNA damage. Here we demonstrate that depletion of XRCC1, a scaffolding protein with an essential role in base-excision repair (BER), sensitizes cancer cells to PARG inhibition. XRCC1 deficient cells exhibit increased nuclear PAR foci in response to PARG inhibition even in the absence of DNA damaging agents. Inhibition of PARP1 with RNAi or small molecule inhibitors rescues cell growth inhibition and reduces the amount of cellular PAR accumulation in PARG inhibitor treated cells. This indicates that the cellular growth inhibition is dependent upon cellular PAR levels, demonstrating selectivity of the small molecule inhibitors for PARG. We hypothesized that inhibition of PAR hydrolysis could result in depletion of cellular NAD as this could prevent recycling of PAR to NAD. Consistent with this hypothesis, PARG inhibition enhanced NAD depletion after treatment of cells with the DNA damaging agent methyl methanesulfonate (MMS). Live cell imaging of XRCC1 depleted cells treated with a PARG inhibitor revealed that cells have large membrane protrusions, similar to the morphology of cells that have been treated with a NAMPT inhibitor, which results in depletion of cellular NAD. Furthermore, addition of the NAD precursor, nicotinamide mononucleotide (NMN) rescued proliferation of PARG inhibited cells. Taken together, these data support a hypothesis in which PARG inhibitors are cytotoxic to sensitive cancer cells via depletion of NAD, ultimately starving the cell of ATP. Thus, PARG inhibition is a novel strategy for exploiting synthetic lethality in cancer cells. The defects that sensitize cancer cells to PARG inhibition are distinct from those that sensitize to PARP inhibitors, namely defects in homology directed repair. Approximately 15% of breast cancer samples exhibit low or no XRCC1 by IHC. A subset (approximately 35%) of the XRCC1 low patient samples also have defects in BRCA1, suggesting that the majority of XRCC1 low tumors may not be responsive to PARP inhibitors. Small molecule PARG inhibitors are currently being evaluated for efficacy in XRCC1 low xenograft models. Citation Format: Leenus Martin, Tzuling Cheng, Dominic I. James, Habiba Begum, Kate M. Smith, Allan Jordan, Ian Waddell, Kedar Vaidya, Marcus Fischer, Bing Yao, Jason Drummond, Leah Cleary, Ruben Martinez, James Sutton, Nandini Ravindran, James Joseph, Eleni Venetsanakos, Michael Dillon, Jeffrey H. Hager, Lisa D. Belmont. PARG inhibitors exhibit synthetic lethality with XRCC1 deficiency and a cellular mechanism of action that is distinct from PARP inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1943.

Background: Constitutive activation of RET kinase activity following mutation or rearrangement can lead to the development of cancers such as medullary thyroid carcinoma and lung adenocarcinoma. The currently approved therapeutics for these diseases are significantly compromised due to dose-limiting toxicities associated with off-target activity vs KDR (VEGFR2) and lack of potency vs anticipated secondary resistance (e.g., gatekeeper) mutations. Consequently there is considerable interest in the development of highly selective inhibitors targeting diverse RET alterations including the putative resistance mutation, V804M. Methods: We have established a robust screening cascade complemented by structure-enabled drug design and effective medicinal chemistry. Biochemical activity vs RET, KDR, and RETV804M protein was assessed using a HTRF assay. Cellular activity was quantified in BaF3 cells dependent on activity of RET, KDR, or RETV804M for proliferation. Tumor growth inhibition and supporting PK/PD studies were carried out in a number of disease-relevant models including a KIF5B-RET lung cancer patient-derived xenograft (PDX) model, a medullary thyroid carcinoma (MZ-CRC-1) xenograft model, and a lung cancer control (Calu-6) xenograft model. Results: Using this optimized, robust platform, we have identified a number of selective compounds offering a range of interesting biochemical and cellular profiles, targeting either, or both, RET and the gatekeeper mutant, RETV804M. We believe certain examples of these compounds offer the first cell-active RETV804M-selective derivatives. More importantly perhaps, we have also delivered a highly selective preclinical candidate compound demonstrating potency vs both RET fusion and RETV804M. This compound is well tolerated in vivo after oral dosing at up to 80mg/kg bid and, in a KIF5B-RET lung cancer PDX model, demonstrates efficacy at much lower doses: 50% tumor regression at 20mg/kg bid and 92% tumor growth inhibition at 10mg/kg bid. Importantly, this agent shows no efficacy in the (non-RET driven) Calu-6 xenograft model, demonstrating selective inhibition of the RET kinase domain. Conclusions: We believe that the identification of well-tolerated, selective RET inhibitors with potent activity against diverse RET alterations (including the anticipated resistance mutation, V804M) offers a clear therapeutic advantage over the present clinically approved compounds. Our most advanced compound fulfills all of these challenging criteria and has now entered preclinical development. Citation Format: Mandy Watson, Rebecca Newton, Ben Acton, Helen Small, Habiba Begum, Samantha Hitchin, Paul Kelly, Donald Ogilvie, Ian Waddell, Allan Jordan. Delivery of a potent, selective, and efficacious RET inhibitor for the treatment of RET-driven lung adenocarcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A123.

Activating gene fusions in the RET receptor tyrosine kinase have been found to drive 1-2% of lung adenocarcinomas and therefore offer an attractive target for targeted therapy. Whilst non-selective tyrosine kinase inhibitors with RET activity are efficacious in this setting, their use is generally limited by dose limiting toxicity associated with their more potent activity versus other targets, specifically KDR (VEGFR2) in the case of cabozantinib and vandetanib. Given this limitation, there is considerable interest in developing more selective inhibitors of RET kinase. Tyrosine kinase inhibitors are prone to early clinical failure due to mutations in the kinase ATPase binding domain, which render the kinase catalytically active but no longer sensitive to drug treatment. Such mutations often occur in the so-called “gatekeeper” region and in this specific case, resistance is predicted to arise from a Val-Met or Val-Leu mutation at residue 804. Through a combination of computational methods, structural biology and drug design, we have identified and further optimized a series of inhibitors of the V804M mutant RET kinase which show sub-micromolar cellular activity in cells driven by V804M RET. Moreover, these agents show excellent selectivity against the wtRET kinase and KDR. As such, these agents may offer valuable start-points for second-generation RET inhibitors for use in patents who relapse after treatment with first generation selective RET inhibitors. Citation Format: Allan M. Jordan, Rebecca Newton, Bohdan Waszkowycz, Richard Bayliss, Habiba Begum, Daniel Burschowsky, Aude Echalier, Samantha Hitchin, Colin Hutton, Shaun Johns, Stuart Jones, Li-Ying Lin, Mark Richards, Chitra Seewooruthun, Alex Stowell, Ian Waddell, Mandy Watson, Donald Ogilvie. Delivering selective and cell-active inhibitors of V804M mutant RET kinase through structure-guided drug discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3236. doi:10.1158/1538-7445.AM2017-3236

Background: The aim of this CRUK-MI Drug Discovery project is to deliver a RET-selective inhibitor for the treatment of cancers with RET activating mutations, which include 1-2% of lung adenocarcinomas and medullary thyroid cancers (MTC). Recent data supports the hypothesis that the efficacy of vandetanib and cabozantinib, clinically approved multi-kinase inhibitors, is limited by toxicities associated with potent activity against KDR. Therefore, a RET-selective inhibitor would represent a best-in-class agent for the treatment of these cancers. Methods: We have established a robust screening cascade to develop a potent, selective RET inhibitor and developed several in vivo models to evaluate compound PKPD and antitumor efficacy. Tumor growth inhibition and PKPD studies were carried out in BaF3 mouse allograft models overexpressing KIF5B-RET or RETV804M and other disease relevant models, including an MTC xenograft (MZ-CRC-1), a KIF5B-RET lung cancer patient derived xenograft (PDX) model (CTG-0838, Champions Oncology) and a lung cancer control xenograft (Calu-6). Results: Two orally bioavailable compounds displaying nanomolar RET potency and >10 fold selectivity over KDR in cellular assays were selected from the lead series and further evaluated in our in vivo PD and efficacy models. Both compounds demonstrated efficacy in the BaF3 KIF5B-RET driven model (71% and 103% tumor growth inhibition (TGI), respectively), accompanied by reduced levels of pRET in the tumor tissue. Following further lead optimisation; a compound displaying an improved DMPK profile and additional nanomolar potency versus the gatekeeper mutation (RETV804M) was identified and accelerated through our DMPK/in vivo cascade. We consider this additional activity versus RETV804M beneficial since mutations at the gatekeeper residue in other tyrosine kinases (e.g. EGFR) have been shown to mediate acquired drug resistance in the clinic. This compound demonstrated significant TGI of 58% and 82% respectively in the BaF3 KIF5B-RET and BaF3 RETV804M allograft models. Moreover, tumor growth in the lung cancer PDX model was strongly inhibited (95% TGI) and tumor regression induced in the MTC xenograft model (109% TGI). As expected, this potent and selective RET inhibitor was not active in the Calu-6 model, which is sensitive to KDR inhibition, whereas vandetanib, a potent KDR inhibitor, significantly inhibited tumor growth (84% TGI). Additional in vitro and in vivo DMPK analyses further support the nomination of this compound as a preclinical candidate. Conclusions: The identification of selective RET inhibitors with significant in vivo activity and minimal toxicity may overcome the limitations of the currently available clinical compounds. We have made considerable progress towards this goal and show here the compelling data supporting our nomination of a preclinical development compound. Citation Format: Mandy Watson, Helen Small, Ben Acton, Habiba Begum, Samantha Hitchin, Allan Jordan, Paul Kelly, Rebecca Newton, Ian Waddell, Gina Paris, Donald Ogilvie. A potent and selective RET inhibitor with efficacy in RET-driven mouse models of medullary thyroid carcinoma and lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2092. doi:10.1158/1538-7445.AM2017-2092

not availableJ Bangladesh Coll Phys Surg 2014; 32: 112-113

RET (REarranged during Transfection) is a receptor tyrosine kinase, which plays pivotal roles in regulating cell survival, differentiation, proliferation, migration and chemotaxis. Activation of RET is a mechanism of oncogenesis in medullary thyroid carcinomas where both germline and sporadic activating somatic mutations are prevalent. At present, there are no known specific RET inhibitors in clinical development, although many potent inhibitors of RET have been opportunistically identified through selectivity profiling of compounds initially designed to target other tyrosine kinases. Vandetanib and cabozantinib, both multi-kinase inhibitors with RET activity, are approved for use in medullary thyroid carcinoma, but additional pharmacological activities, most notably inhibition of vascular endothelial growth factor - VEGFR2 (KDR), lead to dose-limiting toxicity. The recent identification of RET fusions present in ~1% of lung adenocarcinoma patients has renewed interest in the identification and development of more selective RET inhibitors lacking the toxicities associated with the current treatments. In an earlier publication [Newton et al, 2016; 1] we reported the discovery of a series of 2-substituted phenol quinazolines as potent and selective RET kinase inhibitors. Here we describe the development of the robust screening cascade which allowed the identification and advancement of this chemical series. Furthermore we have profiled a panel of RET-active clinical compounds both to validate the cascade and to confirm that none display a RET-selective target profile.

Background:RET is a receptor tyrosine kinase (RTK) and forms part of a macromolecular receptor complex containing dimerised RET receptor, two co-receptors and a bound ligand. Signalling networks downstream of RET play an important role in regulating cell survival, differentiation, proliferation, migration and chemotaxis. Activating mutations in RET (e.g. C634W and M918T) are known drivers in medullary thyroid carcinomas (MTC). More recently, oncogenic RET fusions (e.g. CCDC6-RET and KIF5B-RET) have been identified in 1-2% of lung adenocarcinoma patients. We are currently developing novel, selective inhibitors of RET, and at the same time, investigating a number of biomarker approaches for the stratification of RET fusion-positive lung cancer patients who might benefit from such therapy. Methods: We have undertaken collaborative studies using established techniques including immunohistochemistry (IHC) and FISH (DNA break apart and RNA). In addition, we have investigated hybrid capture DNA sequencing of both biopsy material and circulating tumour DNA in the blood. Here we, compare and contrast the benefits of each biomarker assay evaluated and consider how these approaches could be translated for use in Phase I clinical trials at The Christie. Conclusion: Our data supports the successful implementation of predictive biomarkers to identify patients who might benefit from treatment with selective RET inhibitors. Acknowledgements:This work was funded by Cancer Research UK (Grant numbers C480/A1141 and C5759/A17098). Citation Format: Mandy Watson, Helen Small, Phil Chapman, Gemma Hopkins, Habiba Begum, Ian D. Waddell, Garry Ashton, Caron Abbey, Jade Harris, Mahmood Ayub, Sumitra Mohan, Dominic Rothwell, Ged Brady, Caroline Dive, Allan Jordan, Donald Ogilvie. RET inhibition: Development of novel compounds and a personalized medicine strategy in lung adenocarcinoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A176.