Higher-order modular regulation of the human proteome.

Operons are transcriptional modules that allow bacteria to adapt to environmental changes by coordinately expressing the relevant set of genes. In humans, biological pathways and their regulation are more complex. If and how human cells coordinate the expression of entire biological processes is unclear. Here, we capture 31 higher-order co-regulation modules, which we term progulons, by help of supervised machine-learning on proteomics data. Progulons consist of dozens to hundreds of proteins that together mediate core cellular functions. They are not restricted to physical interactions or co-localisation. Progulon abundance changes are primarily controlled at the level of protein synthesis and degradation. Implemented as a web app at www.proteomehd.net/progulonFinder, our approach enables the targeted search for progulons of specific cellular processes. We use it to identify a DNA replication progulon and reveal multiple new replication factors, validated by extensive phenotyping of siRNA-induced knockdowns. Progulons provide a new entry point into the molecular understanding of biological processes.

Detection of acquired radioresistance in breast cancer cell lines using Raman spectroscopy and machine learning.

Radioresistance-a living cell's response to, and development of resistance to ionising radiation-can lead to radiotherapy failure and/or tumour recurrence. We used Raman spectroscopy and machine learning to characterise biochemical changes that occur in acquired radioresistance for breast cancer cells. We were able to distinguish between wild-type and acquired radioresistant cells by changes in chemical composition using Raman spectroscopy and machine learning with 100% accuracy. In studying both hormone receptor positive and negative cells, we found similar changes in chemical composition that occur with the development of acquired radioresistance; these radioresistant cells contained less lipids and proteins compared to their parental counterparts. As well as characterising acquired radioresistance in vitro, this approach has the potential to be translated into a clinical setting, to look for Raman signals of radioresistance in tumours or biopsies; that would lead to tailored clinical treatments.

Putative molecular markers of Plasmodium falciparum resistance to antimalarial drugs in malaria parasites from Ghana.

Introduction: Antimalarial drugs including artemisinin-based combination therapy (ACT) regimens and sulphadoxine-pyrimethamine (SP) are used in Ghana for malaria therapeutics and prophylaxis respectively. The genetic basis of Plasmodium falciparum development of drug resistance involves single nucleotide polymorphisms in genes encoding proteins for multiple cellular and metabolic processes. The prevalence of single nucleotide polymorphisms in nine P. falciparum genes linked to ACT and SP resistance in the malaria parasite population was determined. Methods: Archived filter paper blood blot samples from patients aged 9 years and below with uncomplicated malaria reporting at 10 sentinel sites located in three ecological zones for the Malaria Therapeutic Efficacy Studies were used. The samples used were collected from 2007-2018 malaria transmission seasons and mutations in the genes were detected using PCR and Sanger sequencing. Results: In all 1,142 samples were used for the study. For falcipain-2 gene (pffp2), Sanger sequencing was successful for 872 samples and were further analysed. The prevalence of the mutants was 45% (392/872) with pffp2 markers V51I and S59F occurring in 15.0% (128/872) and 3.0% (26/872) of the samples respectively. Prevalence of other P. falciparum gene mutations: coronin (pfcoronin) was 44.8% (37/90); cysteine desulfurase (pfnfs) was 73.9% (68/92); apicoplast ribosomal protein S10 (pfarps10) was 36.8% (35/95); ferredoxin (pffd) was 8.8% (8/91); multidrug resistance protein-1 (pfmrp1) was 95.2.0% (80/84); multidrug resistance protein-2 (pfmrp2) was 91.4% (32/35); dihydrofolate reductase (pfdhfr) was 99.0% (84/85); dihydropteroate synthase (pfdhps) was 72% (68/95). Discussion: The observation of numerous mutations in these genes of interest in the Ghanaian isolates, some of which have been implicated in delayed parasite clearance is of great interest. The presence of these genotypes may account for the decline in the efficacies of ACT regimens being used to treat uncomplicated malaria in the country. The need for continuous monitoring of these genetic markers to give first-hand information on parasite susceptibility to antimalarial drugs to inform policy makers and stakeholders in malaria elimination in the country is further discussed.

The influence of artificial intelligence on the work of the medical physicist in radiotherapy practice: a short review.

There have been many applications and influences of Artificial intelligence (AI) in many sectors and its professionals, that of radiotherapy and the medical physicist is no different. AI and technological advances have necessitated changing roles of medical physicists due to the development of modernized technology with image-guided accessories for the radiotherapy treatment of cancer patients. Given the changing role of medical physicists in ensuring patient safety and optimal care, AI can reshape radiotherapy practice now and in some years to come. Medical physicists' roles in radiotherapy practice have evolved to meet technology for the management of better patient care in the age of modern radiotherapy. This short review provides an insight into the influence of AI on the changing role of medical physicists in each specific chain of the workflow in radiotherapy in which they are involved.

The degree and appropriateness of computed tomography utilization for diagnosis of headaches in Ghana.

INTRODUCTION: Headache is a common and sometimes debilitating medical condition. Patients presenting with no neurologic anomaly, nontraumatic primary headache require careful evaluation before neuroimaging. National Guidelines standardizing exploitation of Computed Tomography (CT), the most utilized imaging modality in this clinical scenario, has not been established in Ghana, a developing country with limited healthcare resources. The country has not also adopted existing guidelines such as the National Institute for Health and Care Excellence (NICE) of the United Kingdom or the Appropriateness Criteria (AC) of the American College of Radiologists (ACR). The purpose of this review was to analyze the propensity of CT utilization for diagnosing headaches against the AC of the ACR and discuss some of the socio-economic inferences thereof. METHODS: This study retrospectively reviewed CT imaging records and clinical data of all patients referred for head CT scans between 1st January 2016 and 31st December 2018 at five major health facilities (four tertiary government hospitals and one private hospital) across Ghana. We isolated all head CT scans performed for the diagnosis of headache for analysis. We analyzed the type of presenting headache, CT findings, gender distribution, pattern of referrals, and head CT appropriateness against the AC of the ACR. RESULTS: A total of 44,218 patients were referred to the five facilities for head CT secondary to diverse indications for the period. All non-trauma cases were 41.7%; trauma cases were 31.6%, the majority (72.3%) were from road traffic accidents. The majority (64.9%) of trauma casualties were males. A total of 11,806 (26.7%) patients were referred for a head CT scan for the diagnosis of headache. The private hospital recorded the highest referrals for head CT scan for diagnosis of headache. The gender distribution of all headache patients was 57.6% females, and 42.4% were males. The age distribution showed 19.3% were children, 71.2% were adults, and the aged constituted 9.4%. The results showed 2.8% significant cranial CT findings of all reviewed headache patients. Pathological findings among the cohort of children were 0.6%.The sources and pattern of referrals showed 57.3% were from the Outpatient Department, 26.6% from the Emergency Department, in-patients' referrals were 9.4%, and specialist consultation was 7.1%. Analysis of CT scans performed against the AC of the ACR, showed 69.0% of headache patients were likely scanned inappropriately. CONCLUSIONS: There is a need to implement international best practice guidelines or develop a national neuroimaging policy to protect patients. Unjustified CT utilization for diagnosis of headaches exposes patients to unnecessary ionizing radiation that can instigate cancer and unnecessary expenditure. Head CT scan for some headache patients with normal neurologic findings may be unnecessary in an emerging country like Ghana. Clinicians must, therefore, be discerning in CT scan requests for the diagnosis of headache.

Electron radiotherapy (IOERT) for applications outside of the breast: Dosimetry and influence of tissue inhomogeneities.

PURPOSE: The purpose of study is to investigate the dosimetry of electron intraoperative radiotherapy (IOERT) of the Intraop Mobetron 2000 mobile LINAC in treatments outside of the breast. After commissioning and external validation of dosimetry, we report in vivo results of measurements for treatments outside the breast in a large patient cohort, and investigate if the presence of inhomogeneities can affect in vivo measurements. METHODS AND MATERIALS: Applicator factors and profile curves were measured with a stereotactic diode. The applicators factors of the 6 cm flat and beveled applicators were also confirmed with radiochromic films, parallel-plate ion chamber and by an external audit performed with ThermoLuminescent Dosimeters (TLDs). The influence of bone on dose was investigated by using radiochromic films attached to an insert equivalent to cortical bone, immersed in the water phantom. In vivo dosimetry was performed on 126 patients treated with IOERT using metal oxide-silicon semiconductor field effect transistors (MOSFETs) placed on the tumor bed. RESULTS: Relatively small differences were found among different detectors for measurements of applicator factors. In the external audit, the agreement with the TLD was mostly within ±0.2%. The largest increase of dose due to the presence of cortical bone insert was +6.0% with energy 12 MeV and 3 cm applicator. On average, in vivo dose was significantly (+3.1%) larger than prescribed dose. CONCLUSION: IOERT in applications outside the breast results in low discrepancies between in vivo and prescribed doses, which can be also explained with the presence of tissue inhomogeneity.