Covalent Organic Frameworks as Potential Drug Carriers and Chemotherapeutic Agents for Ovarian Cancers.

Anticancer drugs are often associated with limitations such as poor stability in aqueous solutions, limited cell membrane permeability, nonspecific targeting, and irregular drug release when taken orally. One possible solution to these problems is the use of nanocarriers of drug molecules, particularly those with targeting ability, stimuli-responsive properties, and high drug loading capacity. These nanocarriers can improve drug stability, increase cellular uptake, allow specific targeting of cancer cells, and provide controlled drug release. While improving the therapeutic efficacy of cancer drugs, contemporary researchers also aim to reduce their associated side effects, such that cancer patients are offered with a more effective and targeted treatment strategy. Herein, a set of nine porous covalent organic frameworks (COFs) were tested as drug delivery nanocarriers. Among these, paclitaxel loaded in COF-3 was most effective against the proliferation of ovarian cancer cells. This study highlights the emerging potential of COFs in the field of therapeutic drug delivery. Due to their biocompatibility, these porous COFs provide a viable substrate for controlled drug release, making them attractive candidates for improving drug delivery systems. This work also demonstrates the potential of COFs as efficient drug delivery agents, thereby opening up new opportunities in the field of sarcoma therapy.

Mitochondria act as a key regulatory factor in cancer progression: Current concepts on mutations, mitochondrial dynamics, and therapeutic approach.

The diversified impacts of mitochondrial function vs. dysfunction have been observed in almost all disease conditions including cancers. Mitochondria play crucial roles in cellular homeostasis and integrity, however, mitochondrial dysfunctions influenced by alterations in the mtDNA can disrupt cellular balance. Many external stimuli or cellular defects that cause cellular integrity abnormalities, also impact mitochondrial functions. Imbalances in mitochondrial activity can initiate and lead to accumulations of genetic mutations and can promote the processes of tumorigenesis, progression, and survival. This comprehensive review summarizes epigenetic and genetic alterations that affect the functionality of the mitochondria, with considerations of cellular metabolism, and as influenced by ethnicity. We have also reviewed recent insights regarding mitochondrial dynamics, miRNAs, exosomes that play pivotal roles in cancer promotion, and the impact of mitochondrial dynamics on immune cell mechanisms. The review also summarizes recent therapeutic approaches targeting mitochondria in anti-cancer treatment strategies.

Unveiling Preeclampsia Prognosis: Uterine Artery Doppler Indices in Low-Risk Pregnancies.

Background Anticipating preeclampsia's onset is pivotal in mitigating adverse maternal and perinatal outcomes. This study aims to prognosticate preeclampsia within low-risk pregnancies by evaluating uterine artery Doppler indices within the 14-28 week gestation. Methodology An observational cohort comprising 360 low-risk pregnancies (14-28 weeks gestation) underwent serial uterine artery Doppler assessments at 14-20 and 20-28 weeks. Follow-up was extended to delivery to detect preeclampsia incidence. Results Among 360 participants, 56 (15.5%) developed preeclampsia. Sensitivity values for resistance index (RI), pulsatility index (PI), and bilateral notching were 17.6%, 56.25%, and 71%, respectively, during 14-20 weeks. Similarly, during 20-28 weeks, sensitivities for RI, PI, and bilateral notching were 16.6%, 36.8%, and 55.5%, respectively, with specificity exceeding 90%. Notch depth index (NDI) >0.14 emerged as a better predictor of preeclampsia between both intervals (area under the curve = 0.686 and 0.646). Conclusions Bilateral notching during 14-20 weeks and NDI >0.14 within 14-20 and 20-28 weeks indicate preeclampsia susceptibility in low-risk pregnancies. Conversely, uterine artery Doppler indices at 14-28 weeks effectively rule out preeclampsia development, exhibiting a specificity of >90%.

Prevalence of human papillomavirus infection in abnormal pap smears.

Objectives: This study was undertaken to study the prevalence of human papillomavirus (HPV) infection using the polymerase chain reaction (PCR) technique in abnormal cervical pap smears and to correlate the different cytological results with HPV infection. Material and Methods: A total of 1788 cervical pap smears of women more than 30 years of age conducted over a period of 1 year 3 months (June 2015-August 2016) were screened by liquid-based cytology. High-risk (HR)-HPV testing was performed by PCR in abnormal lesions. Inflammatory smears and some atypical squamous cells of undetermined significance (ASCUS)-reactive cases were excluded from HPV testing. Histopathological correlation was done wherever possible. Results: The overall prevalence of the intraepithelial lesions/malignancy was ASCUS. (ASCUS) - 79 (4.42%), atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion (ASC-H) - 10 (0.56%), low-grade squamous intraepithelial lesion (LSIL) - 26 (1.45%), high-grade squamous intraepithelial lesion (HSIL) - 15 (0.84%), squamous cell carcinoma - 5 (0.28%), and adenocarcinoma - 1 case (0.06%). Overall, 136 (7.60%) samples were classified as abnormal. Seventy-seven samples were included for HR-HPV testing - 20 ASCUS, 10 ASC-H, 26 LSIL, 15 HSIL, and 6 malignant cases. A control group of ten samples with normal cervical cytology within the normal limit (Control) (WNLc) was tested for HR-HPV. HR-HPV was detected in 20% of samples of the WNLc group, 45% of the ASCUS group, 70% of the ASC-H group, 73.07% of the LSIL group, 86.67% of the HSIL, and 83.34% of the samples in the malignant group. Overall, HR-HPV was detected in 68.83% of abnormal cervical pap smears. Conclusion: Our study shows that the percentage of HR-HPV-positive case increases with the severity of cytologic morphology. HPV had 4 times higher positivity in squamous intraepithelial lesion as compared to ASCUS.

Comparing FRET Pairs that Report on Intersubunit Rotation in Bacterial Ribosomes.

Mediated by elongation factor G (EF-G), ribosome translocation along mRNA is accompanied by rotational movement between ribosomal subunits. Here, we reassess whether the intersubunit rotation requires GTP hydrolysis by EF-G or can occur spontaneously. To that end, we employ two independent FRET assays, which are based on labeling either ribosomal proteins (bS6 and bL9) or rRNAs (h44 of 16S and H101 of 23S rRNA). Both FRET pairs reveal three FRET states, corresponding to the non-rotated, rotated and semi-rotated conformations of the ribosome. Both FRET assays show that in the absence of EF-G, pre-translocation ribosomes containing deacylated P-site tRNA undergo spontaneous intersubunit rotations between non-rotated and rotated conformations. While the two FRET pairs exhibit largely similar behavior, they substantially differ in the fraction of ribosomes showing spontaneous fluctuations. Nevertheless, instead of being an invariable intrinsic property of each FRET pair, the fraction of spontaneously fluctuating molecules changes in both FRET assays depending on experimental conditions. Our results underscore importance of using multiple FRET pairs in studies of ribosome dynamics and highlight the role of thermally-driven large-scale ribosome rearrangements in translation.

Comparing FRET pairs that report on intersubunit rotation in bacterial ribosomes.

Mediated by elongation factor G (EF-G), ribosome translocation along mRNA is accompanied by rotational movement between ribosomal subunits. Here, we reassess whether the intersubunit rotation requires GTP hydrolysis by EF-G or can occur spontaneously. To that end, we employ two independent FRET assays, which are based on labeling either ribosomal proteins (bS6 and bL9) or rRNAs (h44 of 16S and H101 of 23S rRNA). Both FRET pairs reveal three FRET states, corresponding to the non-rotated, rotated and semi-rotated conformations of the ribosome. Both FRET assays show that in the absence of EF-G, pre-translocation ribosomes containing deacylated P-site tRNA undergo spontaneous intersubunit rotations between non-rotated and rotated conformations. While the two FRET pairs exhibit largely similar behavior, they substantially differ in the fraction of ribosomes showing spontaneous fluctuations. Nevertheless, instead of being an invariable intrinsic property of each FRET pair, the fraction of spontaneously fluctuating molecules changes in both FRET assays depending on experimental conditions. Our results underscore importance of using multiple FRET pairs in studies of ribosome dynamics and highlight the role of thermally-driven large-scale ribosome rearrangements in translation.

Assessment of Median and Mean Survival Time in Cancer Clinical Trials.

This cohort study assesses the relative stability of median and mean survival time estimates reported in cancer clinical trials.

Interplay between Inter-Subunit Rotation of the Ribosome and Binding of Translational GTPases.

Translational G proteins, whose release from the ribosome is triggered by GTP hydrolysis, regulate protein synthesis. Concomitantly with binding and dissociation of protein factors, translation is accompanied by forward and reverse rotation between ribosomal subunits. Using single-molecule measurements, we explore the ways in which the binding of translational GTPases affects inter-subunit rotation of the ribosome. We demonstrate that the highly conserved translation factor LepA, whose function remains debated, shifts the equilibrium toward the non-rotated conformation of the ribosome. By contrast, the catalyst of ribosome translocation, elongation factor G (EF-G), favors the rotated conformation of the ribosome. Nevertheless, the presence of P-site peptidyl-tRNA and antibiotics, which stabilize the non-rotated conformation of the ribosome, only moderately reduces EF-G binding. These results support the model suggesting that EF-G interacts with both the non-rotated and rotated conformations of the ribosome during mRNA translocation. Our results provide new insights into the molecular mechanisms of LepA and EF-G action and underscore the role of ribosome structural dynamics in translation.

Landscape assessment of the cities in the state of Maharashtra: first step towards air quality management (AQM) and strategic implementation of mitigation plans.

OBJECTIVE OF THE STUDY: This study aims to understand the need for landscape assessment of the 18 non-attainment cities in the state of Maharashtra, to understand and rank the cities according to the need and necessity for strategic implementation of air quality management. This air quality management is a National Clean Air Programme initiative to curb the air pollution level in all the highly polluted Indian cities by 20-30% till 2024. METHODOLOGY: The ranking and selection of the cities consisted of a two-phase approach including (a) desk research and (b) field interventions and stakeholders' consultations. The first phase included (ai) review of 18 non-attainment cities in Maharashtra, (aii) identification of suitable indicators to inform prioritisation during the ranking process, (aiii) data collection and analysis of the indicators and (aiv) the ranking of the 18 non-attainment cities in Maharashtra. The second phase, i.e. field interventions included (bi) Mapping of stakeholders and field visits, (bii) the consultations with the stakeholders, (biii) information and data collection and (biv) ranking and selection of cities. On analysing the score obtained from both the approaches a ranking of all the cities is done accordingly. RESULTS AND DISCUSSION: The screening of cities from the first phase gave a possible list of 8 cities-Aurangabad, Kolhapur, Mumbai, Nagpur, Nashik, Navi Mumbai, Pune, Solapur. Further, the second round of analysis involving field interventions and stakeholder consultations was done within the 8 cities to find out the most suitable list of two to 5 cities. The second research analysis gave Aurangabad, Kolhapur, Mumbai, Navi Mumbai and Pune. A more granular stakeholder consultation resulted in the selection of cities like Navi Mumbai and Pune as the cities where implementation of new strategies seemed feasible. INTERVENTION AND ACTIVITIES: New strategic interventions like (a) strengthen the clean air ecosystem/institutions, (b) air quality monitoring and health impact assessment, and (c) skill development to ensure the long-term sustainability of initiatives planned for the cities.

Size fraction of hazardous particulate matter governing the respiratory deposition and inhalation risk in the highly polluted city Delhi.

Delhi has been identified as one of the highly polluted cities in the world and recently associated with the highest population weighted PM2.5 concentration. However, the unavailability of the health risk estimations using long-term data for Indian cities has been pointed out as a hurdle in performing the correct assessment. The present work estimated deposition of particles in different regions of respiratory systems (head airway = 67% deposition for 2.5 µm particles; tracheo-bronchiolar (TB) = 73% deposition for 1.0 µm particles; alveolar (AL) = 17% deposition for 0.5 µm, 0.25 µm, and < 0.25 µm particles) using PM samples collected at a breathing height of 1.5 m near the major ring road in New Delhi (India). The calculated risk index (RI) varied considerably between winter (1.21 ± 0.26 to 1.33 ± 0.50) and pre-monsoon-southwest monsoon months (0.34 ± 0.08 to 0.96 ± 0.27). Respiratory deposition dose of nanosized particles (≤ 500 nm) in the alveoli region of the lung was found to be considerable (35%) indicating the need for understanding the role of these particles in posing health risk. Although the calculated values of risk metric for exposures of PM-associated metals indicated no risk to IIT Delhi population (hazard quotient < 1 and excess risk of getting cancer < 10-6-10-9), continuous monitoring for particles of different sizes at inhalation height are required for protecting human health.

Analysis of Different Routes of Hysterectomy Based on a Prospective Algorithm and Their Complications in a Tertiary Care Institute.

Introduction: Hysterectomy is the most common gynaecological operation worldwide. The objective of the study is to analyze the various routes of hysterectomy and its complications when the decision of route is based on using a prospective algorithm tree. Methodology. It is an observational study to analyze the route of hysterectomy based on using a prospective algorithm. The decision tree is based on pelvic pathology, uterine size, vaginal access, pelvic adhesion, competency of the surgeon, choice of the patient, and complication of different routes of hysterectomy. Data were collected from preoperative, intraoperative, and postoperative records. Demographic factors, indications, routes of hysterectomy, and complications were recorded and analyzed by using SPSS software version 22. Observation. Among the malignant or suspected malignant pathology groups, TAH was performed in 89 cases and TLH was performed in 3 cases. Among the benign disease groups, VH was performed in 137(38.2%) cases, TAH was performed in 118(32.9%) cases, and TLH was performed in 104 (28.9%) cases. Operative time and a number of blood transfusions were significantly less with VH (p value < 0.0001 and 0.004) compared to abdominal and total laparoscopic hysterectomy. Postoperative complication such as fever was more with abdominal hysterectomy (p-value<0.00001) compared to VH and TLH. Vaginal discharge was more with VH and TLH compared to TAH (p value -0.004) and wound infection was more in the abdominal route (p value 0.001). Conclusion: The abdominal route was the route of choice for surgery in malignancy or suspected malignant pathology. In benign pathology, VH was the most common and preferable route of surgery. Complications were found to be minimal with vaginal hysterectomy.

A conjugated 2D covalent organic framework as a drug delivery vehicle towards triple negative breast cancer malignancy.

Cancer, one of the deadliest diseases for both sexes, has always demanded updated treatment strategies with time. Breast cancer is responsible for the highest mortality rate among females worldwide and requires treatment with advanced regimens due to the higher probability of breast cancer cells to develop drug cytotoxicity followed by resistance. Covalent organic framework (COF) materials with ordered nanoscale porosity can serve as drug delivery vehicles due to their biocompatible nature and large internal void spaces. In this research work, we have employed a novel biocompatible COF, TRIPTA, as a drug delivery carrier towards breast cancer cells. It served as a drug delivery vehicle for cisplatin in triple negative breast cancer (TNBC) cells. We have checked the potency of TRIPTA in combating the proliferation of metastatic TNBC cells. Our results revealed that cisplatin loaded over TRIPTA-COF exhibited a greater impact on the CD44+/CD24- cancer stem cell niche of breast cancer. Retarded migration of cancer cells has also been observed with the dual treatment of TRIPTA and cisplatin compared to that of cisplatin alone. Epithelial-mesenchymal transition (EMT) has also been minimized by the combinatorial treatment of cisplatin carried by the carrier material in comparison to cisplatin alone. The epithelial marker E-cadherin is significantly increased in cells treated with cisplatin together with the carrier COF, and the expression of mesenchymal markers such as N-cadherin is lower. The transcriptional factor Snail has been observed under the same treatment. The carrier material is also internalized by the cancer cells in a time-dependent manner, suggesting that the organic carrier can serve as a specific drug delivery vehicle. Our experimental results suggested that TRIPTA-COF can serve as a potent nanocarrier for cisplatin, showing higher detrimental effects on the proliferation and migration of TNBC cells by increasing the cytotoxicity of cisplatin.

Teaching and Learning Medical Professionalism: an Input from Experienced Faculty and Young Graduates in a Tertiary Care Institute.

Introduction: Medical professionalism is of paramount importance especially in today's day and age. This study gives an insight on the preferred methods of teaching and learning professionalism among the young MBBS graduates and experienced faculty in a medical teaching institute. Material and methods: This was an observational study conducted in the Department of Obstetrics and Gynaecology from January 2019 to January 2020. It included 60 interns and 60 faculty members, who were interviewed for nine different methods of teaching and learning professionalism: (a) professional role model; (b) early clinical exposure; (c) recruiting faculty who had compressive training in medical education before joining the medical institute; (d) teaching and assessing communication skills to each student; (e) conducting seminar, didactic lecture and small group discussion; (f) reflective practice; (g) mentorship; (h) faculty development programme; (i) hidden curriculum. Each participant's response was analyzed using Wilcoxon rank-sum test on SPSS software version 22. Results:Interns preferred early clinical exposure, recruiting faculty with prior comprehensive training in medical education and reflective practice as preferred methods, while faculty members preferred teaching and assessing communication skills for every student, early clinical exposure and mentorship. Conclusion:Early clinical exposure, teaching and assessing communication skills, mentorship and reflective practice are the preferred methods of teaching and learning medical professionalism.

Coverage of antenatal iron-folic acid and calcium distribution during pregnancy and their contextual determinants in the northeastern region of India.

Iron-folic acid (IFA) and calcium supplementation are nutritional interventions recommended prophylactically (against maternal anemia and preeclampsia, respectively) to all antenatal mothers in India under basic antenatal care (ANC) services. Using Health Management Information System data (reporting period: 2018-19 to 2020-21), we mapped the coverage of antenatal IFA and calcium distribution across the remote northeastern region of India relative to the number of pregnant women (PW) who registered for ANC, disaggregated by states and districts. Variations in coverage were also investigated by subgroups based on contextual attributes, viz., physiography (hilly/ plateau/ plain), socioeconomic development ("aspirational"/ "non-aspirational") and proportion of early ANC visits (low/ medium/ high). Full course of antenatal IFA and calcium supplements were received by 79.36 (95% CI: 79.31-79.40) and 61.26 (95% CI: 61.21-61.32) PW per 100 ANC registered women, respectively. There was widespread heterogeneity in outreach, with calcium coverage generally trailing behind IFA coverage. Among states, coverage of the two interventions (per 100 ANC registered women) was highest in Assam (97.06 and 78.11 PW, respectively) and lowest in Nagaland (24.87 and 16.77 PW, respectively). At the district-level, the two interventions failed to reach even 50 PW per 100 ANC registered women in 32 (out of 115) districts. The coverage tended to be inferior in districts that were hilly, "non-aspirational" and had low proportion of early ANC visits. The granular information provided by our findings will facilitate monitoring, root cause analyses, microplanning, informed resource allocation and tailoring of locally appropriate solutions to achieve targeted coverage improvements.

Amniotic Fluid Embolism After First-Trimester Abortion.

Amniotic fluid embolism (AFE) may be a rare event in pregnancy, especially after a first-trimester medical termination of pregnancy (MTP). A 35-year-old G3P2L2 came to our outpatient department at six weeks of pregnancy for medical termination of pregnancy and bilateral tubal ligation. After around one hour of surgery, she developed respiratory distress with abdominal distension, hypotension, tachycardia and tachypnoea. On laparotomy, we found ascitic fluid, bowels with petechia, and oozing all over the wounds. Finally, within 24 hours of surgery, she expired. Strong clinical suspicion of AFE should prompt a multidisciplinary team including anaesthesia, respiratory therapy, critical care, and maternal-foetal medicine to be involved in the ongoing care of women with AFE.

Incidence and Outcomes of Gastrointestinal Bleeding in Patients With Percutaneous Mechanical Circulatory Support Devices.

Percutaneous mechanical circulatory support (pMCS) devices are increasingly used in patients with cardiogenic shock as a bridge to recovery or bridge to decision to advanced heart failure therapies. Gastrointestinal bleeding (GIB) is a common complication that can be catastrophic. Because of the paucity of data describing the association of GIB with pMCS, we analyzed this population using the United States National Inpatient Sample database. We performed a retrospective study in patients with pMCS devices who had GIB during the index hospitalization using the National Inpatient Sample. Multivariate logistic regression analysis was performed to determine independent predictors of GIB in these patients. A total of 466,627 patients were included. We observed an overall increase in the incidence of adjusted GIB from 2.9% to 3.5% (p = 0.0025) from 2005 to 2014. In comparison to patients without GIB, those with GIB had significantly higher in-hospital mortality, length of stay, and hospitalization cost. In addition to the usual co-morbid conditions, the presence of small bowel and colonic ischemia, colon cancer, diverticulosis, chronic liver disease, and peptic ulcer disease were noted to be significant predictors of GIB for all (p <0.001). In conclusion, patients with pMCS and GIB have higher in-hospital mortality, longer length of stay, and higher cost of hospitalization. Awareness of patient risk factors for bleeding and gastrointestinal disorders are important before the use of mechanical circulatory support devices because they are associated with a substantially higher risk for bleeding.

Understanding the Correlation between Metabolic Regulator SIRT1 and Exosomes with CA-125 in Ovarian Cancer: A Clinicopathological Study.

Background: Ovarian cancer (OvCa), the deadliest gynaecological malignancy, is associated with poor prognosis and high mortality rate. Ovarian cancer has been related with CA-125 and metabolic reprogramming by SIRT1 leading to metastasis with the involvement of exosomes. Methods: Clinicopathological data of OvCa patients were collected to perform the analysis. Patients' samples were collected during surgery for immunohistochemistry and flow cytometric analysis of SIRT1, HIF-1α, exosomal markers (CD81 and CD63), ki-67, and PAS staining for glycogen deposition. Adjacent normal and tumor tissues were collected as per the CA-125 levels. Results: CA-125, a vital diagnostic marker, has shown significant correlation with body mass index (BMI) (P = 0.0153), tumor type (P = 0.0029), ascites level, ascites malignancy, degree of dissemination, tumor differentiation, FIGO stage, TNM stage, laterality, and tumor size at P < 0.0001. Since significant correlation was associated with BMI and degree of dissemination, as disclosed by IHC analysis, metabolic marker SIRT1 (P = 0.0003), HIF-1α (P < 0.0001), exosomal marker CD81 (P < 0.0001), ki-67 status (P = 0.0034), and glycogen deposition (P <0.0001) were expressed more in tumor tissues as compared to the normal ones. ROC analysis of CA-125 had shown 327.7 U/ml has the best cutoff point with 82.4% sensitivity and specificity of 52.3%. In addition, Kaplan-Meier plots of CA-125 (P < 0.0001), BMI (P = 0.001), degree of dissemination (P < 0.0001), and ascites level (P <0.0001) reflected significant correlation with overall survival (OS). Upon multivariate Cox-regression analysis for overall survival (OS), BMI (P = 0.008, HR 1.759, 95% CI 1.156-2.677), ascites malignancy (P = 0.032, HR 0.336, 95% CI 0.124-0.911), and degree of dissemination (P = 0.004, HR 1.994, 95% CI 1.251-3.178) were significant proving to be independent indicators of the disease. Conclusion: Clinicopathological parameters like BMI, degree of dissemination, and ascites level along with CA-125 can be prognostic factors for the disease. Levels of CA-125 can depict the metabolic and metastatic factors. Thus, by targeting SIRT1 and assessing exosomal concentrations to overcome metastasis and glycogen deposition, individualized treatment strategy could be designed. In-depth studies are still required.

Revealing the nature of optical activity in carbon dots produced from different chiral precursor molecules.

Carbon dots (CDs) are light-emitting nanoparticles that show great promise for applications in biology and medicine due to the ease of fabrication, biocompatibility, and attractive optical properties. Optical chirality, on the other hand, is an intrinsic feature inherent in many objects in nature, and it can play an important role in the formation of artificial complexes based on CDs that are implemented for enantiomer recognition, site-specific bonding, etc. We employed a one-step hydrothermal synthesis to produce chiral CDs from the commonly used precursors citric acid and ethylenediamine together with a set of different chiral precursors, namely, L-isomers of cysteine, glutathione, phenylglycine, and tryptophan. The resulting CDs consisted of O,N-doped (and also S-doped, in some cases) carbonized cores with surfaces rich in amide and hydroxyl groups; they exhibited high photoluminescence quantum yields reaching 57%, chiral optical signals in the UV and visible spectral regions, and two-photon absorption. Chiral signals of CDs were rather complex and originated from a combination of the chiral precursors attached to the CD surface, hybridization of lower-energy levels of chiral chromophores formed within CDs, and intrinsic chirality of the CD cores. Using DFT analysis, we showed how incorporation of the chiral precursors at the optical centers induced a strong response in their circular dichroism spectra. The optical characteristics of these CDs, which can easily be dispersed in solvents of different polarities, remained stable during pH changes in the environment and after UV exposure for more than 400 min, which opens a wide range of bio-applications.