A systematic review on deep learning-based automated cancer diagnosis models.

Deep learning is gaining importance due to its wide range of applications. Many researchers have utilized deep learning (DL) models for the automated diagnosis of cancer patients. This paper provides a systematic review of DL models for automated diagnosis of cancer patients. Initially, various DL models for cancer diagnosis are presented. Five major categories of cancers such as breast, lung, liver, brain and cervical cancer are considered. As these categories of cancers have a very high percentage of occurrences with high mortality rate. The comparative analysis of different types of DL models is drawn for the diagnosis of cancer at early stages by considering the latest research articles from 2016 to 2022. After comprehensive comparative analysis, it is found that most of the researchers achieved appreciable accuracy with implementation of the convolutional neural network model. These utilized the pretrained models for automated diagnosis of cancer patients. Various shortcomings with the existing DL-based automated cancer diagnosis models are also been presented. Finally, future directions are discussed to facilitate further research for automated diagnosis of cancer patients.

Targeting OGG1 arrests cancer cell proliferation by inducing replication stress.

Altered oncogene expression in cancer cells causes loss of redox homeostasis resulting in oxidative DNA damage, e.g. 8-oxoguanine (8-oxoG), repaired by base excision repair (BER). PARP1 coordinates BER and relies on the upstream 8-oxoguanine-DNA glycosylase (OGG1) to recognise and excise 8-oxoG. Here we hypothesize that OGG1 may represent an attractive target to exploit reactive oxygen species (ROS) elevation in cancer. Although OGG1 depletion is well tolerated in non-transformed cells, we report here that OGG1 depletion obstructs A3 T-cell lymphoblastic acute leukemia growth in vitro and in vivo, validating OGG1 as a potential anti-cancer target. In line with this hypothesis, we show that OGG1 inhibitors (OGG1i) target a wide range of cancer cells, with a favourable therapeutic index compared to non-transformed cells. Mechanistically, OGG1i and shRNA depletion cause S-phase DNA damage, replication stress and proliferation arrest or cell death, representing a novel mechanistic approach to target cancer. This study adds OGG1 to the list of BER factors, e.g. PARP1, as potential targets for cancer treatment.

Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy.

Activated RAS GTPase signalling is a critical driver of oncogenic transformation and malignant disease. Cellular models of RAS-dependent cancers have been used to identify experimental small molecules, such as SCH51344, but their molecular mechanism of action remains generally unknown. Here, using a chemical proteomic approach, we identify the target of SCH51344 as the human mutT homologue MTH1 (also known as NUDT1), a nucleotide pool sanitizing enzyme. Loss-of-function of MTH1 impaired growth of KRAS tumour cells, whereas MTH1 overexpression mitigated sensitivity towards SCH51344. Searching for more drug-like inhibitors, we identified the kinase inhibitor crizotinib as a nanomolar suppressor of MTH1 activity. Surprisingly, the clinically used (R)-enantiomer of the drug was inactive, whereas the (S)-enantiomer selectively inhibited MTH1 catalytic activity. Enzymatic assays, chemical proteomic profiling, kinome-wide activity surveys and MTH1 co-crystal structures of both enantiomers provide a rationale for this remarkable stereospecificity. Disruption of nucleotide pool homeostasis via MTH1 inhibition by (S)-crizotinib induced an increase in DNA single-strand breaks, activated DNA repair in human colon carcinoma cells, and effectively suppressed tumour growth in animal models. Our results propose (S)-crizotinib as an attractive chemical entity for further pre-clinical evaluation, and small-molecule inhibitors of MTH1 in general as a promising novel class of anticancer agents.

MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool.

Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bind in the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.

Global survey of the immunomodulatory potential of common drugs.

Small-molecule drugs may complement antibody-based therapies in an immune-oncology setting, yet systematic methods for the identification and characterization of the immunomodulatory properties of these entities are lacking. We surveyed the immumomodulatory potential of 1,402 small chemical molecules, as defined by their ability to alter the cell-cell interactions among peripheral mononuclear leukocytes ex vivo, using automated microscopy and population-wide single-cell image analysis. Unexpectedly, ∼10% of the agents tested affected these cell-cell interactions differentially. The results accurately recapitulated known immunomodulatory drug classes and revealed several clinically approved drugs that unexpectedly harbor the ability to modulate the immune system, which could potentially contribute to their physiological mechanism of action. For instance, the kinase inhibitor crizotinib promoted T cell interactions with monocytes, as well as with cancer cells, through inhibition of the receptor tyrosine kinase MSTR1 and subsequent upregulation of the expression of major histocompatibility complex molecules. The approach offers an attractive platform for the personalized identification and characterization of immunomodulatory therapeutics.

Severe maternal morbidity and maternal near miss in a tertiary hospital of Delhi.

Background: In addition to maternal mortality, information on maternal near miss and severe maternal morbidity are important in maternal healthcare. We aimed to determine the incidence, causes and outcome of severe maternal morbidity and near miss, and the sociodemographic and obstetric factors associated with these at a tertiary care teaching hospital in Delhi. Methods: Women admitted with severe maternal morbidity and near miss, as defined by the WHO study group, were included in the study. The incidence ratio of near miss and severe morbidity in the hospital was determined, and a case-control study was conducted to study the factors associated with the occurrence of near miss. Information was obtained from hospital records and interviews, using a semi-structured open-ended questionnaire. Results: The incidence ratio of near miss was 6.85/ 1000, and severe morbidity was 11.38/1000 live births. Hypertensive disorders and haemorrhage were the common causes of cases of near miss and severe morbidity. Coagulation dysfunction (62%) was the most common organ dysfunction, followed by uterine dysfunction (22%). Older age (odds ratio [OR] 2.01, confidence interval [CI] 1.02-3.93), the absence of formal education (OR 2.05, CI 1.11-3.75), <18 years of age at marriage (OR 2.01, CI 1.21-3.32), lower income (OR 3.8, CI 1.88-7.64), gravida of four or more (OR 2.25, CI 1.21-4.17) and residence outside Delhi (OR 9.31, CI 4.36-19.90) were significant predictors of near miss. Sepsis, hypertensive disorders and haemorrhage were the most common underlying conditions in women who died. The foetal outcome was a live birth in 64% of near-miss cases and 62% among severe morbidity. Conclusions: The burden of severe maternal morbidity and near miss is high. These need to be identified and managed at the earliest.

Outcome of extraocular retinoblastoma in a resource limited center from low middle income country.

Retinoblastoma (RB) is the most common ocular malignancy in children, and is managed by multimodal treatment. There is a paucity of data regarding the clinical profile and outcome of children with extraocular retinoblastoma from Low Middle Income Countries (LMIC) including India. Case records of children with newly diagnosed extraocular RB from January 2013 to August 2016 treated at our unit were analysed for clinical profile, treatment, and outcome. Over the 44 month study period, 91 children were diagnosed with RB, out of which 41 had extraocular disease. While 26 children had extraocular spread limited to orbit (IRSS stage III), 15 had a distant spread to brain (IRSS stage IV). Median lag period for diagnosis was eight months. Treatment abandonment rates were 38.5% and 46.6% in International Retinoblastoma Staging System (IRSS) stage III and IV respectively. With a median follow up of 31.5 months, the projected overall survival for IRSS III at one, two, and three years was 87.5%, 55.6%, and 39.7%. All patients with stage IV disease died after a median follow up duration of three months. High treatment abandonment rates and limited availability of resources lead to suboptimal survival in children with extraocular RB from LMIC. Initiatives aimed at improving early diagnosis, so that the disease is detected in the intraocular stage, are critical to improve the survival in children with RB.

Stress, anxiety, and depression among call handlers employed in international call centers in the national capital region of Delhi.

BACKGROUND: Call handlers employed in call centers repeatedly undergo stress in their day-to-day lives and this can have deleterious effects on their health. OBJECTIVES: The objectives were to study the levels of stress, anxiety, and depression, and their predictors among call handlers employed in international call centers in the National Capital Region (NCR) of Delhi. MATERIALS AND METHODS: A cross-sectional questionnaire-based survey was conducted among 375 call handlers aged 18-39 years. Depression Anxiety Stress Scale- 42 (DASS-42) was used to measure stress, anxiety, and depression along with a pretested sociodemographic questionnaire. Univariate analysis was done to find out the association of stress, anxiety, and depression with various factors. Variables with P < 0.25 were included in multiple logistic regression and three models were developed each for stress, anxiety, and depression. RESULTS: The prevalence of stress, anxiety, and depression among call handlers was 46.7%, 57.1%, and 62.9% respectively. Abnormal sleep quality, prolonged travel time, and lack of relaxation facilities at the office were predictors of stress and depression. The presence of physical ailments, the absence of hobbies, temporary/part-time employment, and traveling long-distance to office were significant predictors of anxiety among call handlers. CONCLUSION: Call handlers face a high burden of stress, anxiety, and depression. Public health specialists need to pay adequate attention to their health problems.

A high-content phenotypic screen reveals the disruptive potency of quinacrine and 3',4'-dichlorobenzamil on the digestive vacuole of Plasmodium falciparum.

Plasmodium falciparum is the etiological agent of malignant malaria and has been shown to exhibit features resembling programmed cell death. This is triggered upon treatment with low micromolar doses of chloroquine or other lysosomotrophic compounds and is associated with leakage of the digestive vacuole contents. In order to exploit this cell death pathway, we developed a high-content screening method to select compounds that can disrupt the parasite vacuole, as measured by the leakage of intravacuolar Ca(2+). This assay uses the ImageStream 100, an imaging-capable flow cytometer, to assess the distribution of the fluorescent calcium probe Fluo-4. We obtained two hits from a small library of 25 test compounds, quinacrine and 3',4'-dichlorobenzamil. The ability of these compounds to permeabilize the digestive vacuole in laboratory strains and clinical isolates was validated by confocal microscopy. The hits could induce programmed cell death features in both chloroquine-sensitive and -resistant laboratory strains. Quinacrine was effective at inhibiting field isolates in a 48-h reinvasion assay regardless of artemisinin clearance status. We therefore present as proof of concept a phenotypic screening method with the potential to provide mechanistic insights to the activity of antimalarial drugs.

Mitotic MTH1 inhibitor TH1579 induces PD-L1 expression and inflammatory response through the cGAS-STING pathway.

The mitotic MTH1 inhibitor TH1579 is a dual inhibitor that inhibits mitosis and incorporation of oxidative DNA damage and leads to cancer-specific cell death. The response to immune checkpoint inhibitor (ICI) treatment is often augmented by DNA damaging agents through the cGAS-STING pathway. This study investigates whether TH1579 can improve the efficacy of immune checkpoint blockades through its immunomodulatory properties. Various human and murine cancer cell lines were treated with mitotic MTH1i TH1579, and the expression of PD-L1 and T-cell infiltration-related chemokines was analysed by flow cytometry and real-time qPCR. Syngeneic mouse models were established to examine the combined effect of TH1579 and PD-L1 blockade. In our investigation, we found that TH1579 upregulates PD-L1 expression at both the protein and mRNA levels in human cancer cell lines. However, in murine cell lines, the increase was less pronounced. An in vivo experiment in a syngeneic mouse melanoma model showed that TH1579 treatment significantly increased the efficacy of atezolizumab, an anti-PD-L1 antibody, compared to vehicle or atezolizumab monotherapy. Furthermore, TH1579 exhibited immune-modulatory properties, elevating cytokines such as IFN-ß and chemokines including CCL5 and CXCL10, in a cGAS-STING pathway-dependent manner. In conclusion, TH1579 has the potential to improve ICI treatment by modulating immune checkpoint-related proteins and pathways.

A palliative approach for rehabilitation of a pediatric patient with retinoblastoma.

Retinoblastoma is a highly malignant neoplasm. Most of the cases are usually far advanced at the time of detection, requiring enucleation to salvage the child's life. However, the cosmetic rehabilitation of these patients should always be an integral part of their treatment, which helps in their re-integration in the society. This paper presents a case of 5-year-old patient who had undergone enucleation of her left eye due to retinoblastoma. A multidisciplinary approach, including ophthalmologist, psychotherapist, and a prosthodontist, was adopted to meet her physical, psychological, functional, emotional, social, and cosmetic demands. The patient was rehabilitated cosmetically with precisely fabricated ocular prosthesis. An ocular prosthesis is a highly positive and non-invasive approach to improve the cosmetic appearance and psychological well-being of patient.

Level of non-conventional lipid parameters and its comparative analysis with TSH in subclinical hypothyroidism.

OBJECTIVES: The objective of this study is to estimate lipid parameters in subclinical hypothyroidism and correlate it with TSH. METHODS: Forty newly diagnosed cases of subclinical hypothyroidism and Forty age and gender-matched healthy controls were recruited for the study. Blood samples were collected from them and serum lipid profile (i.e. HDL, LDL, TG, serum total cholesterol) of the subjects was estimated by standard photometric methods in a fully auto-analyzer (MINDRAY BS-300) using commercially available kits and VLDL cholesterol was calculated using the Friedewald's formula. While serum Ox-LDL, Lipoprotein A, Apolipoprotein A1 and Apo B were estimated by using commercial kit based on enzyme-linked immmunosorbent assay. RESULTS: The parameters such as Oxidized low-density lipoprotein (Ox-LDL), lipoprotein (a), apolipoprotein A1, apolipoprotein B and small dense lipoprotein (sd LDL) were significantly increased in subclinical hypothyroid cases when compared with the control subjects (p<0.0001). In present study results showed significant positive correlations of serum thyroid stimulating hormone (TSH) with Ox-LDL (r=0.85, p<0.01), sd LDL (r=0.71, p<0.01). CONCLUSIONS: The present study focuses on the role of Ox-LDL, sd-LDL Lipoprotein A, Apolipoprotein A1 and Apo B that are sensitive indicators of atherogenic dyslipidemia in subclinical hypothyroidism and can serve as a better & novel risk factor for CAD.

The novel DNA alkylating agent BO-1090 suppresses the growth of human oral cavity cancer in xenografted and orthotopic mouse models.

Oral cancer is the fourth-most common cause of death in males and overall the sixth-most common cause of cancer death in Taiwan. Surgery, radiotherapy and chemotherapy combined with other therapies are the most common treatments for oral cavity cancer. Although cisplatin, 5-fluorouracil and docetaxel are commonly used clinically, there is no drug specific for oral cavity cancer. Here, we demonstrated that derivatives of 3a-aza-cyclopenta[a]indene, a class of newly synthesized alkylating agents, may be drugs more specific for oral cancer based on its potent in vitro cytotoxicity to oral cancer cells and on in vivo xenografts. Among them, BO-1090, bis(hydroxymethyl)-3a-aza-cyclopenta[a]indene derivative, targeted DNA for its cytotoxic effects as shown by inhibition of DNA synthesis (bromodeoxyuridine-based DNA synthesis assay), induction of DNA crosslinking (alkaline gel shift assay), and induction of DNA single-stranded breaks (Comet assay) and double-stranded breaks (γ-H2AX focus formation). Following DNA damage, BO-1090 induced G1/S-phase arrest and apoptosis in oral cancer cell lines. The therapeutic potential of BO-1090 was tested in mice that received a xenograft of oral cavity cancer cell lines (SAS or Cal 27 cells). Intravenous injection of BO-1090 significantly suppressed tumor growth in comparison to control mice. BO-1090 also significantly reduced the tumor burden in orthotopic mouse models using SAS cells. There was no significant adverse effect of BO-1090 treatment with this dosage based on whole blood count, biochemical enzyme profiles in plasma and histopathology of various organs in mouse. Taken together, our current results demonstrate that B0-1090 may have potential as a treatment for oral cavity cancer.

Synthesis of tunable and multifunctional Ni-doped near-infrared QDs for cancer cell targeting and cellular sorting.

Here, we report the facile preparation of tunable magnetic Ni-doped near-infrared (NIR) quantum dots (MNIR-QDs) as an efficient probe for targeting, imaging, and cellular sorting applications. We synthesized the MNIR-QDs via a hot colloidal synthesis approach to yield monodisperse and tunable QDs. These hydrophobic QDs were structurally and compositionally characterized and further functionalized with amino-PEG and carboxyl-PEG to improve their biocompatibility. Since QDs are known to be toxic due to the presence of cadmium, we have evaluated the in vitro and in vivo toxicity of our surface-functionalized MNIR-QDs. Our results revealed that surface-functionalized MNIR-QDs did not exhibit significant toxicity at the concentrations used in the experiments and are therefore suitable for biological applications. For further in vitro applications, we covalently linked folic acid to the surface of amino-PEG-coated MNIR-QDs through NHS chemistry to target the folate receptors largely present in the HeLa cells to demonstrate the specific targeting and magnetic behavior of these MNIR-QDs. Improved specificity has been observed with treatment of HeLa cells with the folic acid-linked amino PEG-coated MNIR QDs (FA-PEG-MNIR-QDs) compared to the one without folic acid. Since the synthesized probe has magnetic property, we have also successfully demonstrated sorting between the cells which have taken up the probe with the use of a magnet. Our findings strongly suggest that these functionalized MNIR-QDs can be a potential probe for targeting, cellular sorting, and bioimaging applications.

Development of chitosan oligosaccharide-modified gold nanorods for in vivo targeted delivery and noninvasive imaging by NIR irradiation.

In the present study, we demonstrate the synthesis and applications of multifunctional gold nanorod-based probes for specific targeting and noninvasive imaging based on localized heating generated by gold nanorods after NIR irradiation. The structural design of the probe consists of MUA (11-mercaptoundecanoic acid)-capped gold nanorods covalently linked with low-molecular-weight chitosan oligosaccharide (M(w) ~5000) via carbodiimide (EDC) coupling agent. This surface modification is performed for complete replacement of toxic CTAB (hexadecyltrimethyl-ammonium chloride) and acid-responsive delivery of gold nanorods in acidic environment as known to be present at tumor surrounding areas. The resulting chitosan oligosaccharide-modified gold nanorods (CO-GNRs) were further conjugated with tumor targeting monoclonal antibody against EGFR (epidermal growth factor receptor) to provide localized targeting functionality owing to the overexpression of EGFR in human oral adenosquamous carcinoma cell line CAL 27. Initial in vitro and in vivo toxicity assessments indicated that CO-GNRs did not induce any significant toxicity and are thus suitable for biological applications. Furthermore, selective targeting and accumulation of CO-GNRs were observed in vitro via two-photon luminescence imaging studies in CAL 27, which was also observed through in vivo targeting studies performed via NIR (near-infrared) laser irradiation in CAL 27 xenografts of BALB/c nude mice. Hence, the CO-GNRs that we have developed are biocompatible and nontoxic and can be a potential candidate for in vivo targeted delivery, noninvasive imaging based on localized hyperthermia, and photothermal-related therapies.

Generation of a Bessel beam of variable spot size.

We report the generation of a zero-order Bessel beam of continuously variable spot size using a simple optical setup. We have used a pair of metal axicon mirrors to generate a hollow beam of variable dark diameter. This beam was subsequently focused by a convex lens to get a Bessel beam of variable spot size. We also studied the effect of a hollow-beam ring width on nondiffracting propagation range of the generated beam.

Functional Transnasal Endoscopic Conjunctivorhinostomy.

The various surgical options for lacrimal tract reconstruction include canaliculodacryocystorhinostomy; fundal transposition; Conjunctivodacrocystorhinostomy with Jones tube; and in extreme cases conjunctivo-rhinostomy (CR) for total lacrimal bypass. The first three require partial lacrimal tract presence/ integrity while CR is indicated when the canaliculi and/or sac are nonfunctional. This report describes a novel technique of minimally invasive CR through a predominantly endoscopic endonasal approach and further discusses its advantages over other established techniques.

A Study on the Serum γ-Glutamyltranspeptidase and Plasma Osteopontin in Alcoholic Liver Disease.

Background Alcoholic liver disease (ALD) is a major source of alcohol-related morbidity and mortality. Heavy drinkers and alcoholics may progress from fatty liver to alcoholic hepatitis to cirrhosis. The enzyme γ-glutamyltranspeptidase (GGT) is a membrane-bound glycoprotein which catalyzes the transfer of the γ-glutamyl group from γ-glutamyl peptides to other peptides, amino acids, and water. Serum GGT activity mainly attributed to hepatobiliary system and thus is an important marker of ALD. Hence the present study is conducted to estimate and correlate the levels of GGT and osteopontin (OPN) in ALD. Aims and Objectives The objective of this study is to estimate and correlate the levels of GGT and OPN in ALD. Materials and Methods Sixty clinically diagnosed cases of ALD and sixty age- and gender-matched healthy controls were recruited for the study. Blood samples were collected from them and serum aspartate aminotransferase, serum alanine transaminases (ALTs), serum ALP levels, and plasma OPN levels were measured. Estimation of serum aspartate transaminases (AST), ALTs, and alkaline phosphatase (ALP) was assayed by standard photometric methods in autoanalyzer ERBA-XL (EM-200) using commercially available kits. OPN was estimated by using commercial kit based on enzyme-linked immunosorbent assay. Results The parameters of the liver function tests such as AST, ALT, and ALP were significantly increased in patients with ALD ( p < 0.001) when compared with the healthy control subjects. In the present study, significantly increased levels of γ-glutamyl transferases and OPN were found in patients with ALD ( p < 0.001) when compared with the control subjects. OPN showed significant positive correlations with AST ( r = 0.76, p < 0.001), ALT ( r = 0.64, p < 0.001), ALP ( r = 0.68, p < 0.001), and GGT ( r = 0.61, p < 0.001). Conclusion The present study focuses on the role of GGT and OPN that are sensitive indicators of liver cell injury and are most helpful in recognizing hepatocellular diseases such as ALD, hepatitis, and liver cirrhosis. Hence, the pattern of the GGT and OPN levels elevation can be helpful diagnostically.