Discovery of Selective Tertiary Amide Inhibitors of Cyclin-Dependent Kinase 2 (CDK2).

Cyclin-dependent kinases (CDKs) are key regulators of the cell cycle and are frequently altered in cancer cells, thereby leading to uncontrolled proliferation. In this context, CDK2 has emerged as an appealing target for anticancer drug development. Herein, we describe the discovery of a series of selective small molecule inhibitors of CDK2 beginning with historical compounds from our ERK2 program (e.g., compound 6). Structure-based drug design led to the potent and selective tool compound 32, where excellent selectivity against ERK2 and CDK4 was achieved by filling the lipophilic DFG-1 pocket and targeting interactions with CDK2-specific lower hinge binding residues, respectively. Compound 32 demonstrated 112% tumor growth inhibition in mice bearing OVCAR3 tumors with 50 mg/kg bis in die (BID) oral dosing.

C-Arm a Useful Tool for Surgeons in Reduction of Zygomatic Complex Fracture: A Comparative Study: Article Type-Original Research.

Introduction: Reduction of zygomaticomaxillary (ZMC) fracture is often difficult to evaluate intraoperatively because of it peculiar anatomy and limited accessibility. The purpose of this study is to evaluate the efficacy of use of C-arm as a tool for intraoperative monitoring of ZMC fracture reduction. Materials and Methods: Group I (C-Arm) and Group II (control group) comprised of patients with isolated unilateral displaced Zygomatic complex (ZMC) fractures and having orbital volume change. The efficacy of use of C-arm intra-operatively was evaluated to analyse the reduction of fracture. Results: It was observed that mean change in ocular volume was around 1.07cm2 for Group I and 1.51cm2 in Group II. Thus post-operative eye volume was near to normal in Group I than Group II. The change in ocular volume post-operatively was observed to be statistically significant (p-value < 0.05) in both the groups. Post HOC Tukey statistical analysis determined the intergroup relation in change in eye volume between normal, pre- and post-operative and was found to be statistically significant (p-value < 0.05). The intergroup comparison between Group I and Group II was done using ANOVA statistical analysis and was found to be statistically significant (p-value < 0.05). Discussion: Our study revealed that C-arm is definitively an effective tool in the oral and maxillofacial surgery armamentarium, giving better results with minimal surgical exposure and by eliminating operator related error. Supplementary Information: The online version contains supplementary material available at 10.1007/s12070-022-03221-y.

Utility of clinicoradiological, microbiological, histopathological, and molecular methods in the diagnosis of spinal tuberculosis.

PURPOSE: The diagnosis of STB is mainly based on clinicoradiological observations substantiated by bacterial culture, staining, Gene Xpert, and histopathology. The purpose of the study was to correlate these methods to evaluate the effectiveness in the diagnosis of STB. METHODS: A total of 178 clinicoradiologically suspected cases of STB were included in the study. The specimens for diagnostic workup were collected either during surgery or by CT-guided biopsy. All these specimens were tested for tuberculosis through ZN staining, solid culture, histopathology, and PCR. The sensitivity, specificity, PPV, and NPV of each test were calculated using histopathology as a gold standard. RESULTS: Out of the 178 cases, a total of 15 cases were excluded from this study. Among the remaining 163 cases, TB was diagnosed in 143 [87.73%] on histopathology, 130 [79.75%] on Gene Xpert, 40 [24.53%] on culture, and 23 [14.11%] on ZN stain. The sensitivity, specificity, PPV, and NPV of Gene Xpert were 86.71, 70, 95.38, and 42.42%, respectively. The sensitivity, specificity, PPV, and NPV of AFB culture were 27.97, 100, 100, and 16.26%, respectively. The sensitivity, specificity, PPV, and NPV of AFB stain were 16.08, 100, 100, and 14.29%, respectively. Gene Xpert showed a moderate agreement [Ƙc = 0.4432] with histopathology. CONCLUSION: No single diagnostic modality can ascertain the diagnosis, and it is desirable to have a combination of diagnostic batteries for better results. A combination of Gene Xpert and histopathology aids in early and reliable diagnosis of STB.

Deformity Correction with Interbody Fusion Using Lateral versus Posterior Approach in Adult Degenerative Scoliosis: A Systematic Review and Observational Meta-analysis.

This study was designed to systematically review and meta-analyze the functional and radiological outcomes between lateral and posterior approaches in adult degenerative scoliosis (ADS). Both lateral (lumbar, extreme, and oblique) and posterior interbody fusion (posterior lumbar and transforaminal) are used for deformity correction in patients with ADS with unclear comparison in this cohort of patients in the existing literature. A literature search using three electronic databases was performed to identify studies that reported outcomes of lateral (group L) and posterior interbody fusion (group P) in patients with ADS with curves of 10°-40°. Group P was further subdivided into minimally invasive surgery (MIS-P) and open posterior (Op-P) subgroups. Data on functional, radiological, and operative outcomes, length of hospital stay (LOHS), fusion rates, and complications were extracted and meta-analyzed using the random-effects model. A total of 18 studies (732 patients) met the inclusion criteria. No significant difference was found in functional and radiological outcomes between the two groups on data pooling. Total operative time in the MIS-P subgroup was less than that of group L (233.86 minutes vs. 401 minutes, p <0.05). The total blood loss in group L was less than that in the Op-P subgroup(477 mL vs. 1,325.6 mL, p <0.05). Group L had significantly less LOHS than the Op-P subgroup (4.15 days vs. 13.5 days, p <0.05). No significant difference was seen in fusion rates, but complications were seen except for transient sensorimotor weakness (group L: 24.3%, group P: 5.6%; p <0.05). Complications, such as postoperative thigh pain (7.7%), visceral injuries (2%), and retrograde ejaculation (3.7%), were seen only in group L while adjacent segment degeneration was seen only in group P (8.6%). Lateral approach has an advantage in blood loss and LOHS over the Op-P subgroup. The MIS-P subgroup has less operative time than group L, but with comparable blood loss and LOHS. No significant difference was found in functional, radiological, fusion rates, pseudoarthrosis, and complications, except for transient sensorimotor deficits. Few complications were approach-specific in each group.

Is the facial nerve at risk following surgical correction of mandibular condylar fracture: A systematic review and meta-analysis.

To review the literature on the effect of different surgical approaches on facial nerve injuries. The present systematic review addresses the following focus question: Is the facial nerve at risk following surgical correction of mandibular condylar fracture? Electronic and manual literature searches were conducted on databases:PubMed, ScienceDirect and Google scholar,Cochrane and clinicaltrials.gov for studies published until July 2020 to collect information about the effect of different surgical approaches on facial nerve injuries. Systematic literature review was performed following the prisma guidelines to identify studies. Quantitative retrospective and prospective studies,controlled trials,controlled clinical trials were included;case reports and review articles were excluded from this systematic review. 1500 articles published till July 2020 was identified. 116 articles met inclusion criteria. After applying exclusion criteria seven articles were shortlisted. The level of heterogeneity was observed to be less than 50%, between all parameters for all studies making publication bias to be minimum. On comparing various studies statistically using Z-test for all parameters,it was observed that level of significance was significant for various findings like Displacement/Dislocation of fracture and transient facial nerve weakness was found to be statistically significant between all studies (p-value <0.05). Odd ratio, relative ratio and 95% CI was derived for all parameters recorded for various studies. Due to less number of subjective studies, and variability in study designs and lack of reporting on confounding factors,definitive conclusions on effect of various surgical approaches on facial nerve injury cannot be drawn Future well-designed long-term randomized controlled trials are necessary to reveal the necessary correlation between both the parameters.

Intussusception - A common entity but seldom diagnosed (lesson learnt from case series for family physicians).

Intussusception is one of the common causes of acute abdomen in paediatric age bracket with ileocolic type being the most prevalent. This happens when a proximal segment of bowel (intussusceptum) telescopes into the lumen of the adjacent distal segment (intussuscepiens). Here we report six cases of intussusception in which five were in paediatric age group and one was adult. All children were admitted, resuscitated well, USG abdomen was done to confirm the diagnosis, written and informed consent for surgery and anaesthesia, was taken from parents. However, all were managed successfully by hydrostatic saline reduction under sedation. Only one child had recurrence after one year who was again treated conservatively. Adult case was managed by means of laparotomy by excision of benign polyp being the pathological lead point. We present this case series to analyse the spectrum of presentation, diagnostic and therapeutic options available with review of literature. Since primary care providers and family physicians are first responders, this case series would help them for differential diagnosis and prompt referrals for further management.

A role for music in cataract surgery: a systematic review.

PURPOSE: There have been several studies that explore the anxiolytic effects of music during cataract surgery. This is the first systematic review of literature highlighting the effects of music on patients undergoing cataract surgery without pharmacological anxiolytics. METHODS: A systematic review of literature using PRISMA methodology identified randomized controlled trials involving patients undergoing cataract surgery with music as an intervention during the procedure with outcomes measured using at least one assessment of anxiety level, pain score, satisfaction, or vital sign measurements. Studies using pharmacological anxiolytics or additional pain-relieving medications besides local anesthetic were excluded. RESULTS: Three studies, involving 523 patients, were included with patients undergoing cataract surgery with music intervention. Music intervention during cataract surgery has demonstrated use in reducing perceived pain, reducing anxiety, and improving vitals with increased benefit of reduced heart rate and blood pressures with binaural beat embedded music. CONCLUSIONS: The clinical implications of this review identify non-traditional approaches to reducing anxiety intraoperatively for cataract surgeries, offering clinicians alternatives to minimizing benzodiazepine and medication use risks.

Comparative evaluation of buccal pad of fat with and without bovine collagen membrane in the management of oral submucous fibrosis: A prospective clinical study.

BACKGROUND: Oral submucous fibrosis (OSMF) is a chronic, debilitating disease characterized by juxtaepithelial fibrosis. The present study evaluates the efficacy of buccal fat pad (BFP) and bovine collagen membrane as reconstruction options. MATERIALS AND METHODS: The sample size includes 22 patients between 20 and 60 years, randomly distributed in two groups: Group I in which BFP was used and Group II where BFP with bovine collagen membrane was used after surgical resection of fibrotic bands. The clinical evaluation on postoperative 1st, 3rd, and 5th days and 1st, 2nd, 3rd, 4th, 12th, and 24th weeks subsequently. RESULTS: The mean age in Group I was 27.17 ± 3.157 years and Group II was 37.90 ± 6.657 years. The mean preoperative mouth opening was 9.75 ± 6.717 and 8.90 ± 3.784 mm in Groups I and II, respectively. The mean duration of presenting illness in Group I was 9.75 ± 2.598 years and in Group II was 8.80 ± 1.989 years. There was no significant difference observed between Groups I and II in relation to reduced mouth opening and duration of symptoms (P > 0.05) except for age. No significant difference was observed between both the groups in relation to preoperative pain, burning sensation, cheek stiffness, mucosal suppleness, postoperative infection, and postoperative pain at days 1 and 5 and 1st week. There was a significant difference observed in postoperative pain among both the groups on the 3rd day and 2nd week. CONCLUSION: In the present study, both the groups have proved to give better results, as BFP in the form of interposition material showed rapid epithelization and minimum wound contracture.

Angular deformities of lower limb in children: Correction for whom, when and how?

Angular deformities are common presentations in childhood and adolescent age group. It is important to differentiate a true deformity from a physiological deformity, this requires measurement of the intercondylar and intermalleolar distance. Once a true deformity is diagnosed, the apex of the deformity requires to be established. Lower limb frontal plane deformities are evaluated with a true AP standing radiographs of the entire lower limb from hip to ankle. Mechanical or anatomical axis calculation gives the apex (CORA) as well as the magnitude of deformity. Frontal plane deformities require surgical intervention. In younger children, growth modulation surgery allows correction of the deformity with minimal morbidity and without the need for osteotomy. Older children, adolescents and adults require corrective osteotomy. The corrective osteotomy can be closed wedge, open wedge, or a dome osteotomy. The osteotomy may be stabilized with internal fixation with plate and screws or an intramedullary implant as is dictated by the level of osteotomy and the local bony anatomy. External fixators allow gradual and precise correction of the deformity.

Dry Heat as a Decontamination Method for N95 Respirator Reuse.

A pandemic such as COVID-19 can cause a sudden depletion of the worldwide supply of respirators, forcing healthcare providers to reuse them. In this study, we systematically evaluated dry heat treatment as a viable option for the safe decontamination of N95 respirators (1860, 3M) before their reuse. We found that the dry heat generated by an electric cooker (100 °C, 5% relative humidity, 50 min) effectively inactivated Tulane virus (TV, >5.2-log10 reduction), rotavirus (RV, >6.6-log10 reduction), adenovirus (AdV, >4.0-log10 reduction), and transmissible gastroenteritis virus (TGEV, >4.7-log10 reduction). The respirator integrity (determined on the basis of the particle filtration efficiency and quantitative fit testing) was not compromised after 20 cycles of a 50 min dry heat treatment. On the basis of these results, dry heat decontamination generated by an electric cooker (e.g., rice cookers, instant pots, and ovens) could be an effective and accessible decontamination method for the safe reuse of N95 respirators. We recommend users measure the temperature during decontamination to ensure the respirator temperature can be maintained at 100 °C for 50 min.

Review of Acellular Assays of Ambient Particulate Matter Oxidative Potential: Methods and Relationships with Composition, Sources, and Health Effects.

Oxidative stress is a potential mechanism of action for particulate matter (PM) toxicity and can occur when the body's antioxidant capacity cannot counteract or detoxify harmful effects of reactive oxygen species (ROS) due to an excess presence of ROS. ROS are introduced to the body via inhalation of PM with these species present on and/or within the particles (particle-bound ROS) and/or through catalytic generation of ROS in vivo after inhaling redox-active PM species (oxidative potential, OP). The recent development of acellular OP measurement techniques has led to a surge in research across the globe. In this review, particle-bound ROS techniques are discussed briefly while OP measurements are the focus due to an increasing number of epidemiologic studies using OP measurements showing associations with adverse health effects in some studies. The most common OP measurement techniques, including the dithiothreitol assay, glutathione assay, and ascorbic acid assay, are discussed along with evidence for utility of OP measurements in epidemiologic studies and PM characteristics that drive different responses between assay types (such as species composition, emission source, and photochemistry). Overall, most OP assays respond to metals like copper than can be found in emission sources like vehicles. Some OP assays respond to organics, especially photochemically aged organics, from sources like biomass burning. Select OP measurements have significant associations with certain cardiorespiratory end points, such as asthma, congestive heart disease, and lung cancer. In fact, multiple studies have found that exposure to OP measured using the dithiothreitol and glutathione assays drives higher risk ratios for certain cardiorespiratory outcomes than PM mass, suggesting OP measurements may be integrating the health-relevant fraction of PM and will be useful tools for future health analyses. The compositional impacts, including species and emission sources, on OP could have serious implications for health-relevant PM exposure. Though more work is needed, OP assays show promise for health studies as they integrate the impacts of PM species and properties on catalytic redox reactions into one measurement, and current work highlights the importance of metals, organic carbon, vehicles, and biomass burning emissions to PM exposures that could impact health.

Complexation of Iron and Copper in Ambient Particulate Matter and Its Effect on the Oxidative Potential Measured in a Surrogate Lung Fluid.

We investigated the complexation state of atmospheric iron and copper and its impact on the oxidative potential (OP) of ambient PM2.5 (PM, particulate matter). A novel fractionation scheme was developed to segregate three different fractions of Fe and Cu present in ambient PM2.5: (i) complexed with hydrophobic organic compounds, (ii) complexed with hydrophilic organic compounds, and (iii) free or inorganic metal fraction. A solid phase extraction (C-18) column was used to separate these fractions. The fractionation scheme applied to the ambient PM2.5 samples collected from an urban site showed that up to 70-90% of water-soluble Fe and Cu were complexed with the organic compounds. The capability of the complexes of Fe(II) and Cu(II) with Suwanee river fulvic acid (SRFA), a proxy for the atmospheric organic compounds, to generate reactive oxygen species (ROS) (·OH and H2O2) in a surrogate lung fluid (SLF) was measured. The complex of Fe-SRFA showed a strong synergistic effect in the generation of ·OH in SLF, while that of Cu-SRFA showed an additive effect. Overall, our results indicate that organic complexation of the metals in ambient PM could significantly alter their OP and needs to be considered while assessing their health impacts.

Exploration of Pyrrolobenzodiazepine (PBD)-Dimers Containing Disulfide-Based Prodrugs as Payloads for Antibody-Drug Conjugates.

A number of cytotoxic pyrrolobenzodiazepine (PBD) monomers containing various disulfide-based prodrugs were evaluated for their ability to undergo activation (disulfide cleavage) in vitro in the presence of either glutathione (GSH) or cysteine (Cys). A good correlation was observed between in vitro GSH stability and in vitro cytotoxicity toward tumor cell lines. The prodrug-containing compounds were typically more potent against cells with relatively high intracellular GSH levels (e.g., KPL-4 cells). Several antibody-drug conjugates (ADCs) were subsequently constructed from PBD dimers that incorporated selected disulfide-based prodrugs. Such HER2 conjugates exhibited potent antiproliferation activity against KPL-4 cells in vitro in an antigen-dependent manner. However, the disulfide prodrugs contained in the majority of such entities were surprisingly unstable toward whole blood from various species. One HER2-targeting conjugate that contained a thiophenol-derived disulfide prodrug was an exception to this stability trend. It exhibited potent activity in a KPL-4 in vivo efficacy model that was approximately three-fold weaker than that displayed by the corresponding parent ADC. The same prodrug-containing conjugate demonstrated a three-fold improvement in mouse tolerability properties in vivo relative to the parent ADC, which did not contain the prodrug.

Discovery of Peptidomimetic Antibody-Drug Conjugate Linkers with Enhanced Protease Specificity.

Antibody-drug conjugates (ADCs) have become an important therapeutic modality for oncology, with three approved by the FDA and over 60 others in clinical trials. Despite the progress, improvements in ADC therapeutic index are desired. Peptide-based ADC linkers that are cleaved by lysosomal proteases have shown sufficient stability in serum and effective payload-release in targeted cells. If the linker can be preferentially hydrolyzed by tumor-specific proteases, safety margin may improve. However, the use of peptide-based linkers limits our ability to modulate protease specificity. Here we report the structure-guided discovery of novel, nonpeptidic ADC linkers. We show that a cyclobutane-1,1-dicarboxamide-containing linker is hydrolyzed predominantly by cathepsin B while the valine-citrulline dipeptide linker is not. ADCs bearing the nonpeptidic linker are as efficacious and stable in vivo as those with the dipeptide linker. Our results strongly support the application of the peptidomimetic linker and present new opportunities for improving the selectivity of ADCs.

Pleomorphic adenoma involving soft tissue overlying the anterior border of ramus of the mandible: A rare ectopic presentation.

Ectopic pleomorphic adenoma is a rare presentation in sites other than major and minor salivary glands. In literature, cases of pleomorphic adenoma in the soft tissue of the neck, skin of the external auditory canal, subcutaneous layer of nose, and lymph node of mediastinum have been reported. We report a case of ectopic pleomorphic adenoma localized in the soft tissue over the anterior border of the ramus of left side of the mandible.

Adenoid cystic carcinoma of the floor of the mouth - A rare presentation.

Adenoid cystic carcinoma (ACC) is an unusual salivary gland malignancy that remains poorly understood. It is a slow growing but aggressive neoplasm with a tendency for recurrence. It is characterized by the proliferation of ductal (luminal) and myoepithelial cells in cribriform, tubular, solid, and cystic forms. Standard treatment, including surgery with postoperative radiation therapy, has attained reasonable local control rates, but distant metastases do not allow any improvement in the survival rate. The understanding of the molecular mechanisms driving ACC is quite rudimentary. We present a case of a 55-year-old female diagnosed with ACC involving the floor of the mouth with an aim to present the carcinoma's behavior, immunohistocytochemistry, the staining pattern, its treatment, and prognosis.

Simplified Bryostatin Analogues Protect Cells from Chikungunya Virus-Induced Cell Death.

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus showing a recent resurgence and rapid spread worldwide. While vaccines are under development, there are currently no therapies to treat this disease, except for over-the-counter (OTC) analgesics, which alleviate the devastating arthritic and arthralgic symptoms. To identify novel inhibitors of the virus, analogues of the natural product bryostatin 1, a clinical lead for the treatment of cancer, Alzheimer's disease, and HIV eradication, were investigated for in vitro antiviral activity and were found to be among the most potent inhibitors of CHIKV replication reported to date. Bryostatin-based therapeutic efforts and even recent anti-CHIKV strategies have centered on modulation of protein kinase C (PKC). Intriguingly, while the C ring of bryostatin primarily drives interactions with PKC, A- and B-ring functionality in these analogues has a significant effect on the observed cell-protective activity. Significantly, bryostatin 1 itself, a potent pan-PKC modulator, is inactive in these assays. These new findings indicate that the observed anti-CHIKV activity is not solely mediated by PKC modulation, suggesting possible as yet unidentified targets for CHIKV therapeutic intervention. The high potency and low toxicity of these bryologs make them promising new leads for the development of a CHIKV treatment.

Temporomandibular joint dislocation.

Temporomandibular joint (TMJ) dislocation is an uncommon but debilitating condition of the facial skeleton. The condition may be acute or chronic. Acute TMJ dislocation is common in clinical practice and can be managed easily with manual reduction. Chronic recurrent TMJ dislocation is a challenging situation to manage. In this article, we discuss the comprehensive review of the different treatment modalities in managing TMJ dislocation.

Solitary plasmacytoma of the mandible: A rare case report.

Plasmacytoma is a monoclonal, neoplastic proliferation of plasma cells that usually arises within bone marrow or soft tissue sites. It can involve either a single bone (solitary) or multiple bones. Solitary plasmacytoma has a predisposition for the red marrow-containing axial skeleton and is most frequently seen in the thoracic vertebrae, followed by the ribs, sternum, clavicle, or scapula. Its presence in the jaws is extremely rare. We present a case of a 54-year-old female with a well-defined radiolucency of the body region of the mandible later diagnosed as solitary plasmacytoma.

The cryptophycins as potent payloads for antibody drug conjugates.

The cryptophycins are a potent class of cytotoxic agents that were evaluated as antibody drug conjugate (ADC) payloads. Free cryptophycin analog 1 displayed cell activity an order of magnitude more potent than approved ADC payloads MMAE and DM1. This potency increase was also reflected in the activity of the cryptophycin ADCs, attached via a either cleavable or non-cleavable linker.