Adverse stem cell clones within a single patient’s tumor predict clinical outcome in AML patients

Acute myeloid leukemia (AML) patients suffer dismal prognosis upon treatment resistance. To study functional heterogeneity of resistance, we generated serially transplantable patient-derived xenograft (PDX) models from one patient with AML and twelve clones thereof, each derived from a single stem cell, as proven by genetic barcoding. Transcriptome and exome sequencing segregated clones according to their origin from relapse one or two. Undetectable for sequencing, multiplex fluorochrome-guided competitive in vivo treatment trials identified a subset of relapse two clones as uniquely resistant to cytarabine treatment. Transcriptional and proteomic profiles obtained from resistant PDX clones and refractory AML patients defined a 16-gene score that was predictive of clinical outcome in a large independent patient cohort. Thus, we identified novel genes related to cytarabine resistance and provide proof of concept that intra-tumor heterogeneity reflects inter-tumor heterogeneity in AML

Splicing factor YBX1 mediates persistence of JAK2-mutated neoplasms

Janus kinases (JAKs) mediate responses to cytokines, hormones and growth factors in haematopoietic cells. The JAK gene JAK2 is frequently mutated in the ageing haematopoietic system and in haematopoietic cancers. JAK2 mutations constitutively activate downstream signalling and are drivers of myeloproliferative neoplasm (MPN). In clinical use, JAK inhibitors have mixed effects on the overall disease burden of JAK2-mutated clones, prompting us to investigate the mechanism underlying disease persistence. Here, by in-depth phosphoproteome profiling, we identify proteins involved in mRNA processing as targets of mutant JAK2. We found that inactivation of YBX1, a post-translationally modified target of JAK2, sensitizes cells that persist despite treatment with JAK inhibitors to apoptosis and results in RNA mis-splicing, enrichment for retained introns and disruption of the transcriptional control of extracellular signal-regulated kinase (ERK) signalling. In combination with pharmacological JAK inhibition, YBX1 inactivation induces apoptosis in JAK2-dependent mouse and primary human cells, causing regression of the malignant clones in vivo, and inducing molecular remission. This identifies and validates a cell-intrinsic mechanism whereby differential protein phosphorylation causes splicing-dependent alterations of JAK2-ERK signalling and the maintenance of JAK2(V617F) malignant clones. Therapeutic targeting of YBX1-dependent ERK signalling in combination with JAK2 inhibition could thus eradicate cells harbouring mutations in JAK2

Factors Influencing Anti Epileptic Drug Non-Compliance

Non-compliances to anti epileptic drug therapy is one of the commonest causes of relapse of seizure. The various factors influencing non-compliance in a state government hospital where patients below poverty line are issued free drugs once in 2 weeks are unknown. In this study, 200 adult epilepsy patients consisting 100 complaint and non- complaint in each group were interviewed with a structured questionnaire. The relevant demographic and clinical characteristics such as awareness of altitude towards purchasing the drugs were collected. The data was analyzed using student "t" test and chi square test. The factors influencing non-compliance were, a)difficulty in collecting the drugs once in 2 weeks from the hospital (45% vs. 21%:p value < 0.001), b) Lack of family supported (42%vs.29%:p value < 0.05), c) Mental adverse effects of the drugs (54%vs.33%: value <0.002) and d) Poor motivation. The attitude of the patients was negative towards purchasing drugs even at times of emergency (84% vs. 44%:p value <0.001). Measures to rectify the above factors are suggested

Belief Based Rituals And Their Relevance Towards Comprehensive Epilepsy Management

One hundred consecutive adults with epilepsy attending the outpatient clinic for the first time were interviewed to find out the various belief-based rituals practiced by them for the control of epilepsy. They were compared with a control group consisting an equal number of patients with chronic daily headache. The various rituals practiced by them were 1. Exorcism to expel the demon in 22% of the study and 4% of the control group (p value < 0.00015). 2. Tying "Thayathu" around neck, loin or arm in 29% of the study and 10% of the control group(p value <0.00069), 3. wearing "Kappu" (a metal ring) around wrist in 13% of the study group and none in the control group and 4. Tying "Holi thread" around wrist, neck or loin in 22% of the study group and 10% of the control group(p value>0.021). Any one of the above rituals was performed by 51% of the study group and 17% of the control group (p value <0.0001). Most of the patients who practiced the rituals were from suburban towns and rural areas. The mean delay in seeking medical treatment for epilepsy was 26 months among those who performed rituals and 19 months in the rest. During the ictal phase of the seizure, iron made objects such as key, chain, a rod or pipe was thrust into the hand of 80% of patients by a bystander or a relative for the control of convulsion, without providing first aid. The importance of epilepsy awareness programmes for the rural and suburban community as well as health professionals is stressed

Letter to Editor - Non-equivalence of bioavailability between generic and branded form of Sodium valproate

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Evaluation of the accuracy of cone beam computed tomography for immediate implant placement- A case report

Diagnostic imaging acts as a distinctive method in analyzing and drawing in the appropriate treatment protocol for any procedure. Pertaining to immediate implant placement, determining the bone width and height plays a vital role in the success of the implant therapy. This visualization of the measurements done preoperatively will enhance the treatment by reducing the overall time span of the procedure. Currently, cone beam computed tomography (CBCT) plays a significant role in the preoperative determination of the measurements of the tooth and the bone. This case report is regarding, a 27-year-old male patient reporting to the Department of Oral and Maxillofacial Surgery at Madha Dental College and Hospital, with a chief complaint of fractured crown in relation to the upper left front tooth region. On clinical examination, there was the presence of an endodontically failed and fractured crown in relation to 22. With the interpretation of clinical and radiographic examination, the tooth was categorized under unfavorable prognosis. The patient was given a detailed description of the various treatment procedures available pertaining to that present condition, along with immediate implant placement procedure. Since the patient was young and conscious about his esthetics and accuracy, he opted for placement of immediate implant followed by extraction of the tooth. To accurately determine the length and width, the tooth and socket measurements were preoperatively measured by CBCT. This article evaluates the accuracy of CBCT by comparing the clinical quantity of bone and dimensions of tooth to be extracted and alveolar socket

Difficulties encountered in preauricular approach over retromandibular approach in condylar fracture

Fracture of mandible can be classified according to its anatomical location, in which condylar fracture is the most common one overall and is missed on clinical examination. Due to the unique geometry of the mandible and temporomandibular joint, without treatment the fractures can result in marked pain, dysfunction, and deformity. The condylar fracture may be further classified depending on the sides involved: unilateral/bilateral, depending on the height of fracture: intracapsular (within the head of condyle), extracapsular - head and neck (high condyle fracture), and subcondylar (low condyle fracture), and depending on displacement: nondisplaced, displaced (anteromedially, medially, and lateral), and dislocated. The clinical features include swelling and tenderness over the temporomandibular joint region, restricted mouth opening, and anterior open bite. A 34-year-old male patient reported to the Department of Oral and Maxillofacial Surgery at Madha Dental College and Hospital; suffered fall trauma resulting in bilateral condyle fracture, dentoalveolar fracture in mandible with restricted mouth opening, and anterior open bite

5-Hydroxytryptamine Receptor Stimulation of Mitochondrial Biogenesis

Mitochondrial dysfunction is both a cause and target of reactive oxygen species during ischemia-reperfusion, drug, and toxicant injury. After injury, renal proximal tubular cells (RPTC) recover mitochondrial function by increasing the expression of the master regulator of mitochondrial biogenesis, peroxisome-proliferator-activated-receptor-γ-coactivator-1α (PGC-1α). The goal of this study was to determine whether 5-hydroxytryptamine (5-HT) receptor agonists increase mitochondrial biogenesis and accelerate the recovery of mitochondrial function. Reverse transcription-polymerase chain reaction analysis confirmed the presence of 5-HT2A, 5-HT2B, and 5-HT2C receptor mRNA in RPTC. The 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI; 3–10 μM) increased PGC-1α levels, expression of mitochondrial proteins ATP synthase β and NADH dehydrogenase (ubiquinone) 1β subcomplex 8 (NDUFB8), MitoTracker Red staining intensity, cellular respiration, and ATP levels through a 5-HT receptor and PGC-1α-dependent pathway. Similar effects were observed with the 5-HT2 agonist m-chlorophenylpiperazine and were blocked by the 5-HT2 antagonist 8-[3-(4-fluorophenoxy) propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one (AMI-193). In addition, DOI accelerated the recovery of mitochondrial function after oxidant-induced injury in RPTC. This is the first report to demonstrate 5-HT receptor-mediated mitochondrial biogenesis, and we suggest that 5-HT-agonists may be effective in the treatment of mitochondrial and cell injury