ZEB1-mediated fibroblast polarization controls inflammation and sensitivity to immunotherapy in colorectal cancer.

The EMT-transcription factor ZEB1 is heterogeneously expressed in tumor cells and in cancer-associated fibroblasts (CAFs) in colorectal cancer (CRC). While ZEB1 in tumor cells regulates metastasis and therapy resistance, its role in CAFs is largely unknown. Combining fibroblast-specific Zeb1 deletion with immunocompetent mouse models of CRC, we observe that inflammation-driven tumorigenesis is accelerated, whereas invasion and metastasis in sporadic cancers are reduced. Single-cell transcriptomics, histological characterization, and in vitro modeling reveal a crucial role of ZEB1 in CAF polarization, promoting myofibroblastic features by restricting inflammatory activation. Zeb1 deficiency impairs collagen deposition and CAF barrier function but increases NFκB-mediated cytokine production, jointly promoting lymphocyte recruitment and immune checkpoint activation. Strikingly, the Zeb1-deficient CAF repertoire sensitizes to immune checkpoint inhibition, offering a therapeutic opportunity of targeting ZEB1 in CAFs and its usage as a prognostic biomarker. Collectively, we demonstrate that ZEB1-dependent plasticity of CAFs suppresses anti-tumor immunity and promotes metastasis.

Tissue characterization using axicon probe-assisted common-path optical coherence tomography.

In this work, a common-path optical coherence tomography (OCT) system is demonstrated for characterizing the tissue in terms of some optical properties. A negative axicon structure chemically etched inside the fiber tip is employed as optical probe in the OCT. This probe generates a quality Bessel beam owning a large depth-of-field, ∼700 µm and small central spot size, ∼3 µm. The OCT system is probing the sample without using any microscopic lens. For experimental validation, the OCT imaging of chicken tissue has been obtained along with estimation of its refractive index and optical attenuation coefficient. Afterwards, the cancerous tissue is differentiated from the normal tissue based on the OCT imaging, refractive index, and optical attenuation coefficient. The respective tissue samples are collected from the human liver and pancreas. This probe could be a useful tool for endoscopic or minimal-invasive inspection of malignancy inside the tissue either at early-stage or during surgery.

Elevated ROS levels during the early development of Angelman syndrome alter the apoptotic capacity of the developing neural precursor cells.

Angelman syndrome (AS) is a rare genetic neurodevelopmental disorder caused by the maternally inherited loss of function of the UBE3A gene. AS is characterized by a developmental delay, lack of speech, motor dysfunction, epilepsy, autistic features, happy demeanor, and intellectual disability. While the cellular roles of UBE3A are not fully understood, studies suggest that the lack of UBE3A function is associated with elevated levels of reactive oxygen species (ROS). Despite the accumulating evidence emphasizing the importance of ROS during early brain development and its involvement in different neurodevelopmental disorders, up to date, the levels of ROS in AS neural precursor cells (NPCs) and the consequences on AS embryonic neural development have not been elucidated. In this study we show multifaceted mitochondrial aberration in AS brain-derived embryonic NPCs, which exhibit elevated mitochondrial membrane potential (ΔΨm), lower levels of endogenous reduced glutathione, excessive mitochondrial ROS (mROS) levels, and increased apoptosis compared to wild-type (WT) littermates. In addition, we report that glutathione replenishment by glutathione-reduced ethyl ester (GSH-EE) corrects the excessive mROS levels and attenuates the enhanced apoptosis in AS NPCs. Studying the glutathione redox imbalance and mitochondrial abnormalities in embryonic AS NPCs provides an essential insight into the involvement of UBE3A in early neural development, information that can serve as a powerful avenue towards a broader view of AS pathogenesis. Moreover, since mitochondrial dysfunction and elevated ROS levels were associated with other neurodevelopmental disorders, the findings herein suggest some potential shared underlying mechanisms for these disorders as well.

Antigen loss following CAR-T cell therapy: Mechanisms, implications, and potential solutions.

Chimeric Antigen Receptor T-cell (CAR-T cell) therapy has emerged as a groundbreaking immunotherapeutic approach for treating various hematological malignancies. CAR-T cells are engineered to express synthetic receptors that target specific antigens on cancer cells, leading to their eradication. While the therapy has shown remarkable efficacy, a significant challenge that has been observed in 30%-70% of patients showing recurrent disease is antigen loss or downregulation. We searched PubMed/MEDLINE, EMBASE, and Google scholar for articles on antigen loss/escape following Chimeric antigen receptor T-cell therapy in malignancies. Antigen loss refers to the loss or reduction in the expression of the target antigen on cancer cells, rendering CAR-T cells ineffective. This phenomenon poses a significant clinical concern, as it can lead to disease relapse and limited treatment options. This review explores the mechanisms underlying antigen loss following CAR-T cell therapy, its implications on treatment outcomes, and potential strategies to overcome the problem.

Identification of coumarin - benzimidazole hybrids as potential antibacterial agents: Synthesis, in vitro and in vivo biological assessment, and ADMET prediction.

The direct-linked coumarin-benzimidazole hybrids, featuring aryl and n-butyl substituents at the N1-position of benzimidazole were synthesized through a Knoevenagel condensation reaction. This reaction involved the condensation of 1,2-diaminobenzene derivatives with coumarin-3-carboxylic acids in the presence of polyphosphoric acid (PPA) at 154 °C. The in vitro antibacterial potency of the hybrid molecules against different gram-positive and gram-negative bacterial strains led to the identification of the hybrids 6m and 6p with a MIC value of 6.25 µg/mL against a gram-negative bacterium, Klebsiella pneumonia ATCC 27736. Cell viability studies on THP-1 cells demonstrated that the compounds 6m and 6p were non-toxic at a concentration of 50 µM. Furthermore, in vivo efficacy studies using a murine neutropenic thigh infection model revealed that both compounds significantly reduced bacterial (Klebsiella pneumonia ATCC 27736) counts (more than 2 log) compared to the control group. Additionally, both compounds exhibited favorable physicochemical properties and drug-likeness characteristics. Consequently, these compounds hold promise as lead candidates for further development of effective antibacterial drugs.

Evaluation of prescriptions from tertiary care hospitals across India for deviations from treatment guidelines & their potential consequences.

BACKGROUND OBJECTIVES: Irrational prescribing practices have major consequences on patient safety and also increase the economic burden. Real-life examples of impact of irrational prescription have potential to improve prescribing practices. In this context, the present study aimed to capture and evaluate the prevalence of deviations from treatment guidelines in the prescriptions, potential consequence/s of the deviations and corrective actions recommended by clinicians. METHODS: It was a cross-sectional observational study conducted in the outpatient departments of tertiary care hospitals in India wherein the 13 Indian Council of Medical Research Rational Use of Medicines Centres are located. Prescriptions not compliant with the standard treatment guidelines and incomplete prescriptions with respect to formulation, dose, duration and frequency were labelled as 'prescriptions having deviations'. A deviation that could result in a drug interaction, lack of response, increased cost, preventable adverse drug reaction (ADR) and/or antimicrobial resistance was labelled as an 'unacceptable deviation'. RESULTS: Against all the prescriptions assessed, about one tenth of them (475/4838; 9.8%) had unacceptable deviations. However, in 2667/4838 (55.1%) prescriptions, the clinicians had adhered to the treatment guidelines. Two thousand one hundred and seventy-one prescriptions had deviations, of which 475 (21.9%) had unacceptable deviations with pantoprazole (n=54), rabeprazole+domperidone (n=35) and oral enzyme preparations (n=24) as the most frequently prescribed drugs and upper respiratory tract infection (URTI) and hypertension as most common diseases with unacceptable deviations. The potential consequences of deviations were increase in cost (n=301), ADRs (n=254), drug interactions (n=81), lack of therapeutic response (n=77) and antimicrobial resistance (n=72). Major corrective actions proposed for consideration were issuance of an administrative order (n=196) and conducting online training programme (n=108). INTERPRETATION CONCLUSIONS: The overall prevalence of deviations found was 45 per cent of which unacceptable deviations was estimated to be 9.8 per cent. To minimize the deviations, clinicians recommended online training on rational prescribing and administrative directives as potential interventions.

Visually impaired population from low socioeconomic strata and their oral health status: an observational study.

A significant portion of the world's population suffers from blindness. Despite being a vital part of systemic health, oral health is neglected in such a population. The present study aimed to determine the oral health status of blind individuals in north India and to identify the factors affecting it. Sixty-nine blind students from a local school for the visually impaired were included in the study. A questionnaire was used to record the basic demographic details and oral habits, followed by an oral examination by a single trained dentist to record dental caries, periodontal status and dental trauma. The prevalence of Dental caries was 63.8% (mean 1.43 ± 1.61). Gingival bleeding on probing (BOP) was found in 60.9% of individuals. Dental trauma prevalence was 23.2%, and harmful oral habits were found in 31.9% of individuals. Individuals experiencing a toothache in the last year had a 1.784 times higher risk of dental caries than those who didn't experience a toothache. Individuals having acquired blindness are 2.411 times more prone to dental trauma in comparison to those suffering from congenital blindness. Blind individuals have poor oral health. Toothache in the last one year is an important risk factor for dental caries in such individuals. Acquired blindness makes a person more susceptible to dental trauma than congenital blindness.

Prevalence of most caries-susceptible area on individual primary tooth surface: an observational study.

Due to multifactorial aetiology, tooth surfaces of primary dentition are more prone to dental caries and follow the specific pattern of dental caries which is difficult to control. The proper knowledge of caries-susceptible areas on individual primary teeth surfaces guides the clinician to take early preventive measures to stop the progression of dental caries. This study aims to find the prevalence of caries-susceptible areas on primary teeth surfaces in preschool children and the most commonly affected primary teeth. The study design adopted was a cross-sectional study. A total number of 3720 teeth of 186 preschool children were examined for initial pinpoint caries lesions using World Health Organization (WHO) caries detection criteria. 33 caries-susceptible areas were examined on individual primary tooth surfaces of preschool children who visited the Faculty of Dental Sciences. Each tooth surface was recorded separately and no radiographic examination was done. Obtained data was analysed keeping the level of significance at 5%. The overall prevalence of caries-susceptible area was found significantly higher in the maxillary teeth (Maxillary teeth: 41.7% vs. Mandible teeth: 30.7%; p < 0.001) and anterior teeth (Anterior teeth: 43.7% vs. Posterior teeth: 28.4%; p < 0.001). The prevalence of caries-susceptible area on primary teeth on the right side when compared to left counterparts was similar (Right side-38.6% and left side-38.4%; p = 0.931). Area 2 was the most prevalent area on primary teeth surfaces and primary canine was more prevalent in caries-susceptible areas.

Reflective axicon based energy-efficient extended depth of focus quasi-Bessel beam probe for common-path optical coherence tomography.

This work presents an optical fiber negative/reflective axicon probe that generates an energy-efficient quasi-Bessel beam (QBB) having a central spot (CS) possessing ∼20% of the QBB power. With silver coating around the axicon, the CS power has been increased by ∼45%. The QBB possesses a large depth of field, ∼400µm, with a micron order spot size as obtained experimentally. The probe has further been explored for common-path optical coherence tomography. The probe length has been optimized to minimize the path length difference between the reference and sample signal. With a divergence angle of just 0.013°, the beam provides a lateral resolution of ∼2.5 to ∼16µm for an axial distance of 0.1 to 1.0 mm. The imaging results are presented for standard samples such as onion and Scotch tape.

Anxiety in children: A review on how to address it in the perioperative setting post-pandemic.

In this paper, we review the psychological burden of SARS-CoV-2 on children and how health care workers can play a role in mitigating its mental health impact during anesthetic procedures. We evaluate the societal changes that have affected children over 2 years of the pandemic and the subsequent soaring rates of anxiety and depression reported. Unfortunately, the perioperative setting is a stressful experience at baseline and the addition of COVID-19 has only exacerbated the situation. Anxiety and depression are often linked to maladaptive behavior post-surgery, including increased rates of emergence delirium. Providers can utilize techniques based on developmental milestones, Certified Child Life Specialists, parental presence during induction, and medications to reduce anxiety. As health care workers, we need to recognize and address these concerns as untreated mental health issues can leave long-term consequences for children.

Usage Pattern of Fixed-dose Combinations at ICMR Network of Rational Use of Medicine Centres across India: Recommendations for Policymakers and Prescribers.

AIM: Irrational use of medicines is a global problem. In India, one contributing factor is the availability of a large number of fixed-dose combinations (FDCs). To improve rational use and to strengthen policies, it is important to assess the usage patterns and rationality of FDCs. METHODS: This study was conducted as part of a 1-year prospective cross-sectional analysis of prescriptions in the outpatient clinics of broad specialities from 13 tertiary care hospitals across India. Five most commonly prescribed FDCs in each center were analyzed. In addition, all the prescribed FDCs were classified as per the Kokate Committee classification and it was noted whether any of the FDCs were irrational or banned as per the reference lists released by regulatory authorities. RESULTS: A total of 4,838 prescriptions were analyzed. Of these, 2,093 (43.3%) prescriptions had at least one FDC. These 2,093 prescriptions had 366 different FDCs. Of the 366 FDCs, 241 were rational; 10 were irrational; 14 required further data generation; and the remaining 96 FDCs could not be categorized into any of the above. Vitamins and minerals/supplements, antibacterial for systemic use, and drugs for gastroesophageal reflux disease (GERD) and peptic ulcer were the most used FDCs. CONCLUSION: Based on the finding that some prescriptions contained irrational FDCs, it is recommended that a rigorous, regular, and uniform method of evaluation be implemented to approve/ban FDCs and that prescribers be periodically notified about the status of the bans.

All-fiber negative axicon probe with a Bessel beam for cellular-level low coherence phase microscopy and refractive index measurement.

We demonstrate an all-fiber negative axicon probe with a Bessel beam for low coherence phase microscopy including refractive index measurement of a cellular level sample in reflection mode. The negative axicon chemically incised at the distal end of the optical fiber spawns the Bessel beam. The system provides a phase sensitivity of ∼0.28 mrad and optical path length sensitivity of ∼23 pm in air. The lateral resolution and working distance are found to be ∼3.91 µm and 650 µm to exhibit the performance of the system experimentally. The three-dimensional (3D) phase map of the cheek cell along with the refractive index is obtained from the reflected power spectrum. The combined low coherence phase microscopy and refractive index measurement provides the system with a potential for biological application. Also, the all-fiber probe can be easily integrated as an endoscopic probe.

Device-detected nonsustained ventricular tachycardia in adult congenital heart disease without tetralogy of fallot.

OBJECTIVES: To evaluate any association between non-sustained ventricular tachycardia (NSVT) detected by intra-cardiac device and clinical outcomes in repaired adult congenital heart disease (ACHD) without tetralogy of Fallot (TOF). BACKGROUND: NSVT portends a higher risk of serious ventricular tachyarrhythmia in TOF. However its clinical significance when incidentally detected by implantable cardiac device is not well elucidated in non-TOF ACHD cohort. METHODS: We performed a single center, retrospective, longitudinal follow-up study in repaired ACHD (≥18 years) patients without TOF who hosted a pacemaker or automatic implantable cardiac defibrillator (AICD). The cohort was divided based on presence/absence of device detected NSVT. The primary end-point was a composite of sustained ventricular tachycardia (VT), ventricular fibrillation (VF), or sudden cardiac death (SCD). RESULTS: One hundred fifty eight patients (male 56.3%, median [IQR] age of 35 [28-43] years at last follow-up] with longitudinal post-implant follow-up duration of 8 (5-12) years were included. NSVT was detected in 52 (33%) patients. The primary composite end-point was more frequent in NSVT group [11.5% vs. 2.8%; p = .04]. Patients with NSVT were (i) older at the time of initial implant (age 25 vs. 18 years, p = .011) and more frequently demonstrated (ii) systemic ventricular dysfunction (44% vs. 26%; p = .015), as well as (iii) history of ventriculotomy (38% vs. 21%; p = .017). CONCLUSIONS: In our repaired ACHD cohort, we noted a significant association between device-detected-NSVT and the primary composite end-point of sustained VT/VF or SCD. Systemic ventricular dysfunction and history of ventriculotomy were more frequent in the NSVT group and likely constituted the clinical milieu.

Bessel beam with a micrometer-size central spot and interferometry for small volume bioliquid refractive index measurement.

This work demonstrates an interferometric technique to measure the refractive index (RI) of microliter volume of biosample solutions with the help of an optical fiber negative axicon and Bessel beam with the micrometer-size central spot. The RI measuring device consists of a broadband superluminescent diode (SLD) source along with an optical circulator and spectrometer. The axicon optical fiber probe packaged with a glass slide is connected to a broadband SLD source through an optical circulator, and a drop of microliter bioliquid sample is placed on the packaged probe's head. The reflected light from the glass-liquid interface couples back to the axicon probe and interferes with the reference beam generated at the air-glass interface of the axicon. The interference spectrum is further analyzed by applying the fast Fourier transform to calculate power from the respective interface and solve the Fresnel equation for the RI measurement. The RI of small sample volume ∼2µl of glucose solutions and bovine serum albumin protein solutions are reported as an application of the proposed method. This sensing platform shows promising applications in biomedicine for monitoring small volume various biosample concentrations. We also demonstrate RI measurement of flowing liquid sample using the developed setup in case the design can be considered for microfluidic channel research.

Evaluation of serum glucose-regulated protein 78 (GRP78) as a biomarker of treatment response to bortezomib-based induction regimen in multiple myeloma: A cross-sectional pilot study.

GRP78 overexpression in myeloma cells has been associated with bortezomib resistance in multiple myeloma (MM). However, serum GRP78 as a maker of bortezomib-based treatment response remains unexplored. The objective of the study was to evaluate serum GRP78 levels in MM patients who underwent a bortezomib-based induction regimen. This cross-sectional study included adult MM patients (n=30) who completed at least four cycles of bortezomib-based induction therapy. Healthy volunteers (n=30) and newly diagnosed MM patients (n=19) were also recruited to identify the disease-associated change in GRP78 levels. Serum GRP78 was estimated by ELISA. Surface and intracellular expression of GRP78 in bone marrow plasma cells was evaluated in ten MM patients by flow cytometry. Among 30 MM patients [median (range): 52 (38-68) years; 20 males] who completed at least four cycles of bortezomib-based induction therapy, 20 were responders and 10 were non-responders. Serum GRP78 levels were not significantly different between responders [median (IQR): 5.2 (3.1, 8.0) µg/ml] and non-responders [median (IQR): 4.3 (0.1, 7.1) µg/ml] (p=0.4). Although non-significant (p=0.3), median serum GRP78 was higher in newly diagnosed patients when compared to healthy volunteers. Bone marrow plasma cells ranged from 0.2 to 57.8% in the analyzed samples. Intracellular GRP78 expression in bone marrow plasma cells was higher (1.6 to 5 times) when compared to surface expression. To conclude, serum GRP78 levels vary widely in different MM patient groups but did not correlate with response to a bortezomib-based induction regimen.

Fragment-based discovery of a new class of inhibitors targeting mycobacterial tRNA modification.

Translational frameshift errors are often deleterious to the synthesis of functional proteins and could therefore be promoted therapeutically to kill bacteria. TrmD (tRNA-(N(1)G37) methyltransferase) is an essential tRNA modification enzyme in bacteria that prevents +1 errors in the reading frame during protein translation and represents an attractive potential target for the development of new antibiotics. Here, we describe the application of a structure-guided fragment-based drug discovery approach to the design of a new class of inhibitors against TrmD in Mycobacterium abscessus. Fragment library screening, followed by structure-guided chemical elaboration of hits, led to the rapid development of drug-like molecules with potent in vitro TrmD inhibitory activity. Several of these compounds exhibit activity against planktonic M. abscessus and M. tuberculosis as well as against intracellular M. abscessus and M. leprae, indicating their potential as the basis for a novel class of broad-spectrum mycobacterial drugs.

An echocardiographic finding mimicking tricuspid atresia in a neonate with dilated cardiomyopathy.

We report a neonate with dilated cardiomyopathy and have echocardiographic findings consistent with "functional" tricuspid atresia. There was an echo-bright, plate-like tissue at the tricuspid valve position with no forward flow across it. This report underscores the role of right ventricle intracavitary haemodynamic influence on the tricuspid valve leaflet excursion and demonstrates a phenomenon of "pseudo or functional tricuspid atresia" mimicking tricuspid atresia in a patient with acute presentation of cardiomyopathy.

Anthropogenic disturbance favours generalist over specialist parasites in bird communities: Implications for risk of disease emergence.

Niche theory predicts specialists which will be more sensitive to environmental perturbation compared to generalists, a hypothesis receiving broad support in free-living species. Based on their niche breadth, parasites can also be classified as specialists and generalists, with specialists infecting only a few and generalists a diverse array of host species. Here, using avian haemosporidian parasites infecting wild bird populations inhabiting the Western Ghats, India as a model system, we elucidate how climate, habitat and human disturbance affects parasite prevalence both directly and indirectly via their effects on host diversity. Our data demonstrate that anthropogenic disturbance acts to reduce the prevalence of specialist parasite lineages, while increasing that of generalist lineages. Thus, as in free-living species, disturbance favours parasite communities dominated by generalist versus specialist species. Because generalist parasites are more likely to cause emerging infectious diseases, such biotic homogenisation of parasite communities could increase disease emergence risk in the Anthropocene.

BL-02: a versatile X-ray scattering and diffraction beamline for engineering applications at Indus-2 synchrotron source.

A hard X-ray engineering applications beamline (BL-02) was commissioned recently and started operation in March 2019 at the Indian synchrotron source, Indus-2. This bending-magnet-based beamline is capable of operating in various beam modes, viz. white, pink and monochromatic beam. The beamline utilizes the X-ray diffraction technique in energy-dispersive and angle-dispersive modes to carry out experiments mainly focused on engineering problems, viz. stress measurement, texture measurement and determination of elastic constants in a variety of bulk as well as thin-film samples. An open-cradle six-circle diffractometer with ∼12 kg load capacity allows accommodation of a wide variety of engineering samples and qualifies the beamline as a unique facility at Indus-2. The high-resolution mode of this beamline is suitably designed so as to carry out line profile analysis for characterization of micro- and nano-structures. In the present article the beamline is described starting from the beamline design, layout, optics involved, various operational modes and experimental stations. Experiments executed to validate the beamline design parameters and to demonstrate the capabilities of the beamline are also described. The future facilities to be incorporated to enhance the capabilities of the beamline are also discussed.

Safety of hydroxychloroquine in healthcare workers for COVID-19 prophylaxis.

BACKGROUND & OBJECTIVES: Hydroxychloroquine (HCQ), reported to inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in in vitro studies, has been recommended for prophylaxis of COVID-19 in healthcare workers (HCWs). The objective of this study was to assess short-term adverse events (AEs) of HCQ in HCWs. METHODS: This cross-sectional study among consenting HCWs taking prophylaxis and working in hospitals with COVID-19 patients used online forms to collect details of HCWs, comorbidities, prophylactic drugs used and AEs after the first dose of HCQ. Verification of dose and AEs was done by personal contact. Multivariate logistic regression analysis was done to determine the effect of age, gender and dose of HCQ on AE. RESULTS: Of the 1303 HCWs included, 98.4 per cent (n=1282) took HCQ and 66 per cent (n=861) took 800 mg as first day's dose. Among the 19.9 per cent (n=259) reporting AEs, 1.5 per cent (n=20) took treatment for AE, none were hospitalized and three discontinued HCQ. Gastrointestinal AEs were the most common (172, 13.2%), with less in older [odds ratio (OR) 0.56, 95% confidence interval (CI) 0.35-0.89], with more in females (OR 2.46, 95% CI 1.78-3.38) and in those taking a total dose of 800 mg on day one compared to a lower dose. Hypoglycaemia (1.1%, n=14), cardiovascular events (0.7%, n=9) and other AEs were minimal. INTERPRETATION & CONCLUSIONS: HCQ prophylaxis first dose was well tolerated among HCWs as evidenced by a low discontinuation. For adverse effects, a small number required treatment, and none required hospitalization. The study had limitations of convenience sampling and lack of laboratory and electrocardiography confirmation of AEs.