Evaluation of Protein Identification and Quantification by the diaPASEF Method on timsTOF SCP.

Accurate and precise quantification is crucial in modern proteomics, particularly in the context of exploring low-amount samples. While the innovative 4D-data-independent acquisition (DIA) quantitative proteomics facilitated by timsTOF mass spectrometers gives enhanced sensitivity and selectivity for protein identification, the diaPASEF (parallel accumulation-serial fragmentation combined with data-independent acquisition) parameters have not been systematically optimized, and a comprehensive evaluation of the quantification is currently lacking. In this study, we conducted a thorough optimization of key parameters on a timsTOF SCP instrument, including sample loading amount (50 ng), ramp/accumulation time (140 ms), isolation window width (20 m/z), and gradient time (60 min). To further improve the identification of proteins in low-amount samples, we utilized different column settings and introduced 0.02% n-dodecyl-ß-d-maltoside (DDM) in the sample reconstitution solution, resulting in a remarkable 19-fold increase in protein identification at the single-cell-equivalent level. Moreover, a comprehensive comparison of protein quantification using a tandem mass tag reporter (TMT-reporter), complement TMT ions (TMTc), and diaPASEF revealed a strong correlation between these methods. Both diaPASEF and TMTc have effectively addressed the issue of ratio compression, highlighting the diaPASEF method's effectiveness in achieving accurate quantification data compared to TMT reporter quantification. Additionally, an in-depth analysis of in-group variation positioned diaPASEF between the TMT-reporter and TMTc methods. Therefore, diaPASEF quantification on the timsTOF SCP instrument emerges as a precise and accurate methodology for quantitative proteomics, especially for samples with small amounts.

The Comparison of ChatGPT 3.5, Microsoft Bing, and Google Gemini for Diagnosing Cases of Neuro-Ophthalmology.

OBJECTIVE: We aim to compare the capabilities of ChatGPT 3.5, Microsoft Bing, and Google Gemini in handling neuro-ophthalmological case scenarios. METHODS: Ten randomly chosen neuro-ophthalmological cases from a publicly accessible database were used to test the accuracy and suitability of all three models, and the case details were followed by the following query: "What is the most probable diagnosis?" RESULTS: On the basis of the accuracy of diagnosis, all three chat boxes (ChatGPT 3.5, Microsoft Bing, and Google Gemini) gave the correct diagnosis in four (40%) out of 10 cases, whereas in terms of suitability, ChatGPT 3.5, Microsoft Bing, and Google Gemini gave six (60%), five (50%), and five (50%) out of 10 case scenarios, respectively. CONCLUSION: ChatGPT 3.5 performs better than the other two when it comes to handling neuro-ophthalmological case difficulties. These results highlight the potential benefits of developing artificial intelligence (AI) models for improving medical education and ocular diagnostics.

Altered GM1 catabolism affects NMDAR-mediated Ca2+ signaling at ER-PM junctions and increases synaptic spine formation in a GM1-gangliosidosis model.

Endoplasmic reticulum-plasma membrane (ER-PM) junctions mediate Ca2+ flux across neuronal membranes. The properties of these membrane contact sites are defined by their lipid content, but little attention has been given to glycosphingolipids (GSLs). Here, we show that GM1-ganglioside, an abundant GSL in neuronal membranes, is integral to ER-PM junctions; it interacts with synaptic proteins/receptors and regulates Ca2+ signaling. In a model of the neurodegenerative lysosomal storage disease, GM1-gangliosidosis, pathogenic accumulation of GM1 at ER-PM junctions due to ß-galactosidase deficiency drastically alters neuronal Ca2+ homeostasis. Mechanistically, we show that GM1 interacts with the phosphorylated N-methyl D-aspartate receptor (NMDAR) Ca2+ channel, thereby increasing Ca2+ flux, activating extracellular signal-regulated kinase (ERK) signaling, and increasing the number of synaptic spines without increasing synaptic connectivity. Thus, GM1 clustering at ER-PM junctions alters synaptic plasticity and worsens the generalized neuronal cell death characteristic of GM1-gangliosidosis.

Adherence and acceptability of multiple micronutrient supplementation during pregnancy: Study protocol for a cluster-randomized non-inferiority trial in Cambodia.

BACKGROUND: Iron and folic acid (IFA) supplements are currently provided to Cambodian women during pregnancy. However, recent research has found benefits of a multiple micronutrient supplement (MMS) over just IFA alone on several outcomes of perinatal and infant health. The Ministry of Health in Cambodia has proposed a transition from IFA to MMS but to effectively guide this transition requires implementation research on the acceptability and adherence to MMS (over IFA). METHODS: This non-inferiority trial aims to assess the adherence and acceptability of IFA (60 mg elemental iron and 400 µg folic acid) compared to MMS (standard UNIMMAP formulation including 15 micronutrients) during antenatal care in Cambodia. A prospective cohort of 1545 pregnant women will be assigned to one of three trial arms: (1) IFA for 90 days [IFA-90]; (2) MMS for 180 days with two distributions of 90-count tablet bottles [MMS-90]; or (3) MMS for 180 days with one 180-count tablet bottle [MMS-180]. Each arm will enroll 515 women across 48 health centers (clusters) in Kampong Thom Province in Cambodia. The primary outcome is the non-inferiority of adherence rates of MMS-180 compared to IFA-90, as assessed by tablet counts. Mixed-effects logistic and linear regression models will be used to estimate the difference in the adherence rate between the two groups, with an 'a priori' determined non-inferiority margin of 15%. Acceptability of MMS and IFA will be measured using a quantitative survey conducted with enrolled pregnant women at 30-day, 90-day, and 180-day time-points. DISCUSSION: Findings from this study will guide an effective and feasible MMS scale-up strategy for Cambodia. Additionally, the findings will be shared globally with other stakeholders planning to scale up MMS in other countries. TRIAL REGISTRATION: NCT05867836 ( ClinicalTrials.gov , registered May 18, 2023).

Recurrent mucinous cystic neoplasm of the mesentery in a young nullipara mimicking as ovarian carcinoma.

INRODUCTION: Mucinous cystic neoplasms are rare tumors. They may originate from either ovaries, pancreas, or other intra-abdominal sites, but rarely from the mesentery. CASE HISTORY: A 22-year-old nulliparaous woman, who had undergone laparascopic bilateral cystectomy for recurrent ovarian mass, presented with pain in abdomen, backache, and menstrual irregularities. Provisionally diagnosed as ovarian carcinoma, she underwent bilateral salpingo-oophorectomy and sigmoid colectomy. However, the histopathological examination revealed mucinous cystic neoplasm of the mesentery. DISCUSSION: Thus, complete resection of the cysts with meticulous gross and histopathological examination remains the gold standard to differentiate mucinous cystic neoplasm (MCN) of the mesentery from its mimics, especially malignant counterparts, enabling clinicians to adequately manage such patients. Here, we present a case of recurrent MCN of mesentery (mesocolon), mimicking as ovarian carcinoma confirmed on histopathological examination, in a young adult.

A microdosimetry analysis of reversible electroporation in scattered, overlapping, and cancerous cervical cells.

We present a numerical method for studying reversible electroporation on normal and cancerous cervical cells. This microdosimetry analysis builds on a unique approach for extracting contours of free and overlapping cervical cells in the cluster from the Extended Depth of Field (EDF) images. The algorithm used for extracting the contours is a joint optimization of multiple-level set function along with the Gaussian mixture model and Maximally Stable Extremal Regions. These contours are then exported to a multi-physics domain solver, where a variable frequency pulsed electric field is applied. The trans-Membrane voltage (TMV) developed across the cell membrane is computed using the Maxwell equation coupled with a statistical approach, employing the asymptotic Smoluchowski equation. The numerical model was validated by successful replication of existing experimental configurations that employed low-frequency uni-polar pulses on the overlapping cells to obtain reversible electroporation, wherein, several overlapping clumps of cervical cells were targeted. For high-frequency calculation, a combination of normal and cancerous cells is introduced to the computational domain. The cells are assumed to be dispersive and the Debye dispersion equation is used for further calculations. We also present the resulting strength-duration relationship for achieving the threshold value of electroporation between the normal and cancerous cervical cells due to their size and conductivity differences. The dye uptake modulation during the high-frequency electric field electroporation is further advocated by a mathematical model.

Comprehensive germline profiling of patients with breast cancer: initial experience from a Familial Cancer Clinic.

Introduction: Breast cancer is the most common cancer among Indian females. There is limited data on germline profiling of breast cancer patients from India. Objective: The objective of the current study was to analyse the frequency and spectrum of germline variant profiles and clinicopathological characteristics of breast cancer patients referred to our Familial Cancer Clinic (FCC). Materials and methods: It is a single-centre audit of patients with a confirmed diagnosis of breast carcinoma referred to our FCC from January 2017 to 2020. All patients underwent pretest counselling. Genetic testing was done by multigene panel testing by next-generation sequencing along with reflex multiplication ligation-dependent probe amplification for BRCA1 and 2. The variants were classified based on American College of Medical Genetics guidelines. Demographic and clinicopathological details were extracted from the case record files. Results: One hundred and fifty-five patients were referred to the FCC and underwent pretest counselling. A total of 99 (63.9%) patients underwent genetic testing. Among them, 62 patients (62/99 = 62.6%) had a germline variant. A pathogenic/likely pathogenic (P/LP) germline variant was identified in 41 (41.4%) of the patients who underwent testing. Additional variants of unknown significance (VUS) were identified in seven patients who also carried a P/LP variant. VUS alone was detected in 21 patients (21/99 = 21.2%). Among the P/LP pathogenic variants (PV), BRCA 1 PV were seen in 27 patients (65.8%), BRCA 2 variants in 7 patients (17.1%), ATM variants in 3 patients (7.3%) and RAD51, TP53, CHEK2 and HMMR in 1 patient each. Variants were significantly more common in patients with a family history (FH) of malignancy than those without FH (58.5% versus 29.5%; p = 0.013). Age and triple-negative histology were not found to be significantly associated with the occurrence of P/LP PVs. Conclusion: We report a 41% P/LP variant rate in our selected cohort of breast cancer patients, with variants in BRCA constituting 83% and non-BRCA gene variants constituting 17%.

Quantum Capacitance of Two-Dimensional-Material-Based Supercapacitor Electrodes.

Electrochemical energy storage technology has emerged as one of the most viable solutions to tackle the challenge of fossil-fuel-based technology and associated global pollution. Supercapacitors are widely used for high-power applications, and there is tremendous ongoing effort to make them useful for high-energy storage applications. While electrode materials of supercapacitors play a central role in charge storage performance, insights into the contribution from different charge storage mechanisms are crucial from both fundamental and applied aspects. In this context, apart from the electric double layer and fast redox reaction at/near the surface, another pronounced contribution from the electrode is quantum capacitance (CQ). Here, the origin of CQ, how it contributes to the total capacitance, the possible strategies to improve it, and the state-of-art CQ of electrode materials, including carbon, two-dimensional materials, and their composites, are discussed. Although most of the studies on quantifying CQ are theoretical, some case studies on experimental measurements using standard electrochemical techniques are summarized. With an overview and critical analysis of theoretical studies on quantum capacitance of electrode materials, this review critically examines the supercapacitor design strategies, including choosing the right materials and electrolytes. These insights are also relevant to other types of clean energy storage technologies, including metal-ion capacitors and batteries.

A Neutral Flavin-Triphenylamine Probe for Mitochondrial Bioimaging under Different Microenvironments.

A bioinspired design built around a neutral flavin-triphenylamine core has been investigated for selective mitochondrial bioimaging capabilities in different microenvironments. Significant advantages with respect to long-term tracking, faster internalization, penetrability within the spheroid structures, and strong emission signal under induced hypoxia conditions have been observed, which could offer an alternative to the existing mitotrackers for hypoxia-related biological events.

Bilateral Breast Cancer: Clinical Profile and Management.

There is paucity of literature regarding the demography, histopathology, management, and outcomes of bilateral breast cancer (BBC). We present our experience of treating 127 BBC with multimodality management. An audit of prospectively maintained computerized breast cancer database of the department of surgical oncology at a tertiary care center was performed. Demography, clinical profile, molecular sub-types, treatment patterns, and outcomes were analyzed. A total 127 patients presented with BBC between 1992 and 2019. Ninety-four had metachronous (MBBC) and 33 had synchronous breast cancer (SBBC). Most contralateral breast cancer (CBC) patients had early-stage breast cancer in comparison to the index side cancer (37% vs 32%). Ninety-four patients underwent bilateral mastectomy and only 18 patients underwent bilateral breast conservation. Seventy-one patients undergoing BCS and surgery for LABC were given postoperative radiotherapy. All patients received adjuvant chemo- and/or hormonal therapy both for index and CBC based on the stage and hormone receptor status. Thirty-three percent of patients had either locoregional or distant relapse. The 5-year overall survival (OS) and 5-year disease-free survival (DFS) of the entire cohort were 86.6% and 68.4% respectively. There was no difference in the OS and DFS between SBBC and MBBC. The incidence of BBC is expected to increase with effective diagnostic and therapeutic interventions and improving survival. Patients require individualized treatment planning in a multidisciplinary treatment setting.

A Rare Case of Cytomegalovirus Retinitis in a Young Immunocompetent Patient.

Cytomegalovirus (CMV) is known to be the most common opportunistic infection in immunocompromised cases, and CMV retinitis is the most common ocular manifestation. Severe retinitis with involvement of the macula or retinal necrosis can lead to vision loss. Prompt diagnosis and treatment can restrict the disease's progression. We describe the case of a 30-year-old man who presented with the chief complaint of progressive diminution of vision in both eyes for 15 days. Diminution of vision was associated with fever and skin rashes. The patient had no history of diabetes, hypertension, tuberculosis, ocular trauma, ocular surgery, organ transplant history, history of immunosuppression, or previous drug history except paracetamol tablets for fever. On ocular examination on the day of presentation, the patient's best corrected visual acuity on Snellen's visual acuity chart was 6/12 and 6/24 in the right and left eyes, respectively. Fundus examination revealed a well-defined optic disc with peripapillary flame-shaped hemorrhages with exudates and an epiretinal membrane. On spectral domain optical coherence tomography (SD-OCT), macular edema was 469 µm and 421 µm in the right and left eyes, respectively. On serological examination, only cytomegalovirus IgG came out positive (1196.65 AU/ml). Based on the clinical findings, fundus examination, and lab investigations, the patient was diagnosed as having a systemic CMV infection with CMV retinitis, and treatment was started with intravenous ganciclovir. With timely diagnosis and management, the patient's vision was recovered. This is a rare case report regarding the development of CMV retinitis in a completely immunocompetent individual.

Descriptive Study of Headache as the Most Common Presenting Feature of Cerebral Venous Thrombosis.

OBJECTIVE: To study the etiology and clinical characteristics of cerebral venous thrombosis (CVT) patients with a detailed description of headache as a presenting feature. INTRODUCTION: CVT is an infrequent type of stroke with protean clinical manifestations. The most common presenting symptom in CVT is headache (>85%), followed by seizures and focal neurological deficits. METHODS: A total of 32 consecutive and confirmed patients of CVT were recruited after obtaining informed consent. CVT was diagnosed based on clinical and imaging parameters. Data regarding etiology, clinical symptoms, and signs with special mention of headache pattern, onset, site, character, severity (based on the visual analog scale), aggravating and relieving factors, as well as sinus involvement were recorded. RESULTS: A total of 32 patients (16 males and 16 females) with a mean age of 31.56 (SD = 14.31) years were recruited, out of which 31 patients (96.87%) presented with headaches. The mode of onset of headache was acute in 19.35%, sub-acute in 67.75%, and chronic in 12.9% of patients. Location was holocranial in 38.71%, hemicranial in 29.03%, frontal in 22.58%, and occipital in 9.68% of patients. Headache was severe in 38.7% and moderate in 61.3% of patients. Character was throbbing in 67.74%, heaviness in 25.8%, and band-like in 6.46% of patients. Headache was aggravated on bending forward in 58.06%, movement in 35.48%, coughing in 32.26%, straining in 25.8%, and standing in 16.12% of patients. The relieving factors of headache were lying down in 45.16%, sleeping in 45.16%, and sitting quietly in 9.86% of patients. CONCLUSION: CVT should be suspected in patients presenting with new-onset holocranial or hemicranial headaches of increasing intensity, thereby requiring early imaging and appropriate management.

Assessment of Risk Factor Progression Due to the COVID-19 Pandemic Among Diagnosed Cases of Hypertension and Diabetes Under the Field Practice Area of Urban Primary Health Centre, Rishikesh, Uttarakhand.

INTRODUCTION:  Hypertension and diabetes were the two pertinent comorbidities of non-communicable disease which was most deadly affected during the COVID-19 pandemic, globally. Therefore, the present study was carried out to assess the progression of risk factors in patients with hypertension and diabetes, and behavioural risk factors during the COVID-19 pandemic. MATERIAL AND METHODS: A community-based longitudinal study was carried out for a period of one year in patients with pre-existing hypertension and diabetes in the field practise area of urban primary health centres (UPHC) in Rishikesh. The sample size is estimated to be 274, Only 100 study participants could be enrolled due to the COVID-19 pandemic. A convenience sampling method was used. Data were analysed using SPSS Version 23 (IBM Corp., Armonk, NY). Mean ± SD was calculated for continuous variables. The Chi-square test and the Fischer exact test were employed as appropriate to examine the association. To compare the means, the paired "T-test" was utilised. RESULT: Mean age of 100 study participants was 56 years ± 11SD. A significant difference (p=0.03) in random blood sugar and diastolic blood pressure was observed before and during the pandemic Proportion of tobacco users and alcoholics was 33% and 22%, respectively. The progression of hypertension and diabetes was reported to be significant among the participants with unhealthy diets and unhealthy lifestyles. CONCLUSION: COVID-19 pandemic poses an increase in risk factors like the adoption of unhealthy and sedentary lifestyles, tobacco, and alcohol consumption. All these factors were significantly (p=0.02) associated with the progression of diabetes and hypertension.

No Doppler Single Position-Lateral Intercostal Artery Perforator Flap (NDSP-LICAP): a Safe and Versatile Flap for Breast Oncoplasty in Resource-Limited Setting.

INTRODUCTION: The lateral intercostal artery perforator flap (LICAP) has emerged as one of the safest and less morbid flaps for lateral and central breast defects. We hereby describe a reproducible no Doppler single position (NDSP) technique to harvest it in single position without handheld Doppler, making it a versatile flap for lateral breast defects in resource-limited setting also. MATERIALS AND METHODS: With this technique, we performed a total of 22 LICAP turnover flaps over a period of 18 months from January 2020 to June 2021. In all 22 cases, the indication of flap was to fill the post-breast conservation surgery (BCS) defects in outer quadrant of breast. All LICAP flaps were harvested by surface marking of anatomical landmarks and without handheld Doppler. RESULTS: Out of 22 LICAP turnover flaps, thirteen were harvested for left breast and nine for right breast. The median width and length of the flap were 12.2 cm and 19.6 cm, respectively. The additional mean operative time was 41 min. All LICAP flaps survived well, and grade 1 Clavien-Dindo morbidity was documented in four cases. Mean hospital stay was 2.6 days. All patients received radiotherapy on their stipulated schedule. Early cosmetic outcome was good, and long-term outcomes are awaited. CONCLUSION: NDSP-LICAP flap is a workhorse for lateral breast defects. Precise knowledge of perforators and anatomical landmarks can be used for harvesting these flaps, thus avoiding ultrasound Doppler and dedicated training for perforator localization. This technique has short learning curve without the need for any plastic surgery training. The early cosmetic outcomes are good.

Re-operative surgery for differentiated thyroid cancer: A single institutional experience of 182 cases.

INTRODUCTION: Re-operative thyroid surgery (RTS) is performed in patients of differentiated thyroid cancer (DTC) with residual or recurrent disease. However, there is a paucity of literature discussing experience and technique of RTS. This study aims to address this gap by providing a comprehensive review of RTS for DTC, utilizing experiences from a dedicated complex thyroid surgical oncology program at the apex hospital in a developing country. METHODS: A retrospective analysis was conducted using data from the Department of Surgical Oncology's thyroid cancer database. The study period spanned from 2006 to 2022. Clinical presentation, prior surgical history, operative details of RTS, and post-operative outcomes were assessed. Descriptive analysis was performed. RESULTS: During the study period, a total of 182 patients underwent re-operative thyroid surgery (RTS). The primary surgeries performed prior to RTS included near-total or total thyroidectomy in most cases (69.2%), and approximately half of the patients (48.4%) had prior neck node interventions. The RTS procedures consisted of completion total thyroidectomy in 30.8% of cases and surgery for thyroid bed recurrence in 9.9% of cases, while central node dissection was performed in 46.2% of patients and unilateral or bilateral template neck dissection was performed in 41.8% of cases. Extended resections were required in 9.3% of patients. Post-operative complications included permanent hypoparathyroidism (2.7%) and unilateral recurrent laryngeal nerve palsy (1.6%). CONCLUSIONS: RTS is a complex procedure with high rates of post-operative morbidity reported in literature. Optimal outcomes require a multidisciplinary approach, thorough assessment, and skilled surgeons.

Altered GM1 catabolism affects NMDAR-mediated Ca 2+ signaling at ER-PM junctions and increases synaptic spine formation.

Endoplasmic reticulum-plasma membrane (ER-PM) junctions mediate Ca 2+ flux across neuronal membranes. The properties of these membrane contact sites are defined by their lipid content, but little attention has been given to glycosphingolipids (GSLs). Here, we show that GM1-ganglioside, an abundant GSL in neuronal membranes, is integral to ER-PM junctions; it interacts with synaptic proteins/receptors and regulates Ca 2+ signaling. In a model of the neurodegenerative lysosomal storage disease, GM1-gangliosidosis, pathogenic accumulation of GM1 at ER-PM junctions due to ß-galactosidase deficiency drastically alters neuronal Ca 2+ homeostasis. Mechanistically, we show that GM1 interacts with the phosphorylated NMDAR Ca 2+ channel, thereby increasing Ca 2+ flux, activating ERK signaling, and increasing the number of synaptic spines without increasing synaptic connectivity. Thus, GM1 clustering at ER-PM junctions alters synaptic plasticity and exacerbates the generalized neuronal cell death characteristic of GM1-gangliosidosis.

A Comprehensive Survey on Multi-Agent Reinforcement Learning for Connected and Automated Vehicles.

Connected and automated vehicles (CAVs) require multiple tasks in their seamless maneuverings. Some essential tasks that require simultaneous management and actions are motion planning, traffic prediction, traffic intersection management, etc. A few of them are complex in nature. Multi-agent reinforcement learning (MARL) can solve complex problems involving simultaneous controls. Recently, many researchers applied MARL in such applications. However, there is a lack of extensive surveys on the ongoing research to identify the current problems, proposed methods, and future research directions in MARL for CAVs. This paper provides a comprehensive survey on MARL for CAVs. A classification-based paper analysis is performed to identify the current developments and highlight the various existing research directions. Finally, the challenges in current works are discussed, and some potential areas are given for exploration to overcome those challenges. Future readers will benefit from this survey and can apply the ideas and findings in their research to solve complex problems.

Ascertainment of causes of neonatal death using verbal autopsy in Rishikesh, Uttarakhand: A cross-sectional study.

Background: India shares a huge burden of the total number of global neonatal deaths. The neonatal mortality rate in Uttarakhand is higher in comparison to the national rate. Understanding the causes and contextual factors that contribute to neonatal deaths is critical for developing a health programme and policy. Therefore, this study was aimed to ascertain causes of neonatal deaths using verbal autopsy in Rishikesh, Uttarakhand. Material and Methods: A community-based cross-sectional study was conducted in Rishikesh, Uttarakhand from July 2018 to June 2019. The study participants were mothers or primary caregivers of deceased neonates. The verbal autopsy tool of the National Health Mission, Government of India was used to collect data. All neonatal deaths from July 2018 to June 2019 were included in this study. The cause of neonatal death was ascertained by two independent doctors. Results: A total of 23 neonatal deaths could be traced during July 2018 through June 2019 in Rishikesh. One death was excluded from the study. Sixty-eight percent (15/22) of neonatal deaths occurred in the first week of life. Major causes of neonatal deaths were perinatal asphyxia (7/22), congenital malformation (6/22), and prematurity (4/22). Most (9/22) of the delays were in making a decision to seek medical care for neonates. Conclusion: The major causes of neonatal deaths were perinatal asphyxia, congenital malformation, and prematurity. Most of the deaths occurred during the early neonatal period.

Stromal-induced epithelial-mesenchymal transition induces targetable drug resistance in acute lymphoblastic leukemia.

The bone marrow microenvironment (BME) drives drug resistance in acute lymphoblastic leukemia (ALL) through leukemic cell interactions with bone marrow (BM) niches, but the underlying mechanisms remain unclear. Here, we show that the interaction between ALL and mesenchymal stem cells (MSCs) through integrin ß1 induces an epithelial-mesenchymal transition (EMT)-like program in MSC-adherent ALL cells, resulting in drug resistance and enhanced survival. Moreover, single-cell RNA sequencing analysis of ALL-MSC co-culture identifies a hybrid cluster of MSC-adherent ALL cells expressing both B-ALL and MSC signature genes, orchestrated by a WNT/ß-catenin-mediated EMT-like program. Blockade of interaction between ß-catenin and CREB binding protein impairs the survival and drug resistance of MSC-adherent ALL cells in vitro and results in a reduction in leukemic burden in vivo. Targeting of this WNT/ß-catenin-mediated EMT-like program is a potential therapeutic approach to overcome cell extrinsically acquired drug resistance in ALL.

Metal-Free Direct C3-H Alkylation and Arylation of Quinoxalin-2(1H)-Ones with Inert Alkyl and Aryl Chlorides.

In the present manuscript, we reported the first visible-light-enabled direct C3-H alkylation/arylation of quinoxalin-2(1H)-ones with unactivated alkyl/aryl chlorides under metal-free conditions. A wide range of unactivated alkyl and aryl chlorides containing different functionalities are coupled with a variety of quinoxalin-2(1H)-one derivatives under mild reaction conditions to afford the C3-alkyl/aryl substituted quinoxalin-2(1H)-ones in moderate to good yields.