Optimal systemic treatment and real-world clinical application of ctDNA in patients with metastatic HER2-mutant lung cancer.

INTRODUCTION: No definitive answers currently exist regarding optimal first-line therapy for HER2-mutant NSCLC. Access to rapid tissue sequencing is a major barrier to precision drug development in the first-line setting. ctDNA analysis has the potential to overcome these obstacles and guide treatment. METHODS: We retrospectively analyzed patients with metastatic HER2-mutant NSCLC who underwent prospective clinical ctDNA sequencing and received systemic therapy at Memorial Sloan Kettering Cancer Center (MSK) from January 2016 to September 2022. HER2 mutations were identified by next-generation sequencing through MSK-IMPACT, MSK-ACCESS or Resolution ctDx LungTM assay. Primary endpoints were time to the next treatment (TTNT) and overall survival (OS). RESULTS: Sixty-three patients were included in the primary analysis. Chemoimmunotherapy (33/63, 52.4 %) was the predominant first-line treatment with a median TTNT of 5.1 months (95 %CI 4.1 - 6.1) whereas 55.0 % (22/40) of patients who received second-line T-DXd obtained a median TTNT of 9.2 m (95 % CI, 0-22.2). Plasma ctDNA was tested before first-line therapy in 40 patients with a median OS of 28.0 months (95 % CI 21-34), in whom 31 patients (78.0 %) had detectable ctDNA. HER2 mutations were detected on ctDNA with a median turnaround time of 13 days, occasionally co-occurred with EGFR and MET alterations and were tracked longitudinally correlating with treatment response. Patients with detectable baseline ctDNA had significantly shorter OS (hazard ratio (HR), 5.25; 95 % CI, 1.2-23.9; p = 0.019). CONCLUSION: Chemoimmunotherapy remains a major treatment option for metastatic HER2-mutant NSCLC. ctDNA can rapidly detect HER2 and co-mutations, and it has the potential to guide and monitor optimal first-line therapy. As a negative prognostic biomarker, detectable ctDNA at baseline would need to be taken into account for patient selection in future studies.

DNA liquid biopsy-based prediction of cancer-associated venous thromboembolism.

Cancer-associated venous thromboembolism (VTE) is a major source of oncologic cost, morbidity and mortality. Identifying high-risk patients for prophylactic anticoagulation is challenging and adds to clinician burden. Circulating tumor DNA (ctDNA) sequencing assays ('liquid biopsies') are widely implemented, but their utility for VTE prognostication is unknown. Here we analyzed three plasma sequencing cohorts: a pan-cancer discovery cohort of 4,141 patients with non-small cell lung cancer (NSCLC) or breast, pancreatic and other cancers; a prospective validation cohort consisting of 1,426 patients with the same cancer types; and an international generalizability cohort of 463 patients with advanced NSCLC. ctDNA detection was associated with VTE independent of clinical and radiographic features. A machine learning model trained on liquid biopsy data outperformed previous risk scores (discovery, validation and generalizability c-indices 0.74, 0.73 and 0.67, respectively, versus 0.57, 0.61 and 0.54 for the Khorana score). In real-world data, anticoagulation was associated with lower VTE rates if ctDNA was detected (n = 2,522, adjusted hazard ratio (HR) = 0.50, 95% confidence interval (CI): 0.30-0.81); ctDNA- patients (n = 1,619) did not benefit from anticoagulation (adjusted HR = 0.89, 95% CI: 0.40-2.0). These results provide preliminary evidence that liquid biopsies may improve VTE risk stratification in addition to clinical parameters. Interventional, randomized prospective studies are needed to confirm the clinical utility of liquid biopsies for guiding anticoagulation in patients with cancer.

Millimeter-Wave and Short-Range Wireless Communication Antenna Based on High-Conductivity Graphene-Assembled Film.

Millimeter-wave and short-range wireless communication is an important part of the Internet of Things due to its advantages of high transmission speed and large data capacity. In this paper, two antenna arrays operating at typical millimeter-wave bands (45 and 60 GHz) based on graphene-assembled films (GAF) are proposed for short-range wireless communication application. The 45 GHz graphene-assembled film antenna array is in the form of a magnetoelectric dipole antenna with a strip slot coupling to achieve bidirectional radiation, which offers an operating bandwidth of 40-49.5 GHz with a realized gain of 11.8 dBi. The 60 GHz graphene-assembled film antenna utilizes a microstrip discontinuous radiation array to achieve radiation with an operating bandwidth of 59-64 GHz, reaching the peak realized gain of 14.92 dBi over the working frequency. Finally, we proposed an experimental validation to verify the transmission performance of both antenna arrays in an actual conference room. The results show that the signal drops slowly in the room with drop rates of 0.064 dB/cm (at 45 GHz) and 0.071 dB/cm (at 60 GHz), while it steeply dropped through the wall with the drop rates of 2.3 and 3.13 dB/cm, more than 35-fold difference in signal drop rates in the room and through the wall. It has been confirmed that the proposed antenna arrays can successfully realize fast indoor short-range wireless communication while also preventing signal leakage through walls, thereby enhancing the security of information. In summary, this is the first time that we have applied graphene-based materials to millimeter-wave and short-range wireless communications, revealing the significant potential of carbon-based materials in high-frequency communication systems.

Peripheral T-cell receptor repertoire dynamics in small cell lung cancer.

Background: Identifying a circulating biomarker predictive of immune checkpoint inhibitor (ICI) benefit in patients with small cell lung cancer (SCLC) remains an unmet need. Characteristics of peripheral and intratumoral T-cell receptor (TCR) repertoires have been shown to predict clinical outcomes in non-small cell lung cancer (NSCLC). Recognizing a knowledge gap, we sought to characterize circulating TCR repertoires and their relationship with clinical outcomes in SCLC. Methods: SCLC patients with limited (n=4) and extensive (n=10) stage disease were prospectively enrolled for blood collection and chart review. Targeted next-generation sequencing of TCR beta and alpha chains of peripheral blood samples was performed. Unique TCR clonotypes were defined by identical CDR3, V gene, and J gene nucleotide sequences of the beta chain and subsequently used to calculate TCR diversity indices. Results: Patients with stable versus progressive and limited versus extensive stage disease did not demonstrate significant differences in V gene usage. Kaplan-Meier curve and log-rank analysis did not identify a statistical difference in progression-free survival (PFS) (P=0.900) or overall survival (OS) (P=0.200) between high and low on-treatment TCR diversity groups, although the high diversity group exhibited a trend toward increased OS. Conclusions: We report the second study investigating peripheral TCR repertoire diversity in SCLC. With a limited sample size, no statistically significant associations between peripheral TCR diversity and clinical outcomes were observed, though further study is warranted.

NLRP3 and Gut Microbiota Homeostasis: Progress in Research.

The inflammasome is a platform for inflammatory signaling, and the NLRP3 inflammasome recognizes stimuli in vitro and in vivo, and releases inflammatory cytokines that trigger inflammation and pyroptosis. In the gut, the NLRP3 inflammasome is a key sensor for protecting the body from damage and exogenous pathogens. It plays a fundamental role in maintaining the stability of the gut's immune system. We focus on the role of NLRP3 as a key node in maintaining the homeostasis of gut microbiota which has not been fully highlighted in the past; gut microbiota and innate immunity, as well as the NLRP3 inflammasome, are discussed in this article.

Hydrogen sulfide against preeclampsia exposure-induced oxidative mitochondrial damage in HTR-8/SVneo cells.

Extravillous trophoblast invasion disorder caused by oxidative stress is involved in the pathogenesis of preeclampsia (PE). In order to identify whether hydrogen sulfide (H2S) can prevent oxidative stress injury in extravillous trophoblasts. HTR-8/SVneo cells were detected by H2S inhibiting H2O2 induced oxidative mitochondrial damage. Reactive oxygen species (ROS) were detected, as well as malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD). JC-1 detected the potential of the mitochondrial membrane in this experiment. Then to detect the expression level of the apoptosis-inducing protein B-cell lymphoma-2 (Bcl-2) associated X protein (Bax), caspase 3, p53, p-p53, the apoptosis-inhibiting protein Bcl-2, PRAP, and the mitochondria fission protein Drp1, p-Drp1. CCK-8 assay, it was demonstrated that cell proliferation in the NaHS group was significantly higher than that in the Mod group, indicating that H2S may induce cell proliferation. Transwell assay elucidated that cell invasion in the NaHS group was recovered compared to the Mod group. ROS concentration no matter in cells or mitochondria was decreased by NaHS, which we could get from the comparison between the Mod group, PAG group, and NaHS group. The concentration of MDA was significantly lower in the NaHS group, and the concentration of SOD was extremely high in the NaHS group. Utilized JC-1 to detect mitochondrial membrane potential and found that cells from the NaHS group had a stable potential while cells from the Mod group and PAG group partly lost their potential, which could demonstrate that NaHS could maintain mitochondrial membrane potential. The western blot results revealed that p-Drp1 had a significant decline in the NaHS group, which means mitochondria fission was decreased in the NaHS group. The expression level of Bax and caspase 3 was significantly lower than in the Mod group and PAG group, and the expression level of Bcl-and PRAP was significantly higher in the NaHS group. That could prove that NaHS protect HTR-8/SVneo cell by inhibiting cell apoptosis. These promising results show that H2S elicits its effects on cell apoptosis by decreasing ROS concentration, maintaining mitochondrial membrane stability, and promoting apoptosis-inhibiting protein expression in cells.

Semiquantitative microscopic pore characterizations of the metamorphic rock reservoir in the central paleo-uplift belt, Songliao Basin.

Currently, metamorphic rock is a common target for natural gas exploration, and reservoirs are the key factors restricting natural gas exploration and development in metamorphic rocks. The deep metamorphic rock gas reservoir in the central paleo-uplift of the northern Songliao Basin has good exploration and development potential. In this study, we use a combination of qualitative descriptions and quantitative analysis to comprehensively analyze the pore characteristics of the reservoir and explore the factors controlling the pore characteristics of the metamorphic rock reservoir in the central paleo-uplift belt of the Songliao Basin. The metamorphic rock reservoir in the central paleo-uplift belt contains three types of lithologies: chlorite schist, mica schist and mylonite, each with different protoliths and metamorphic histories. The results of high-pressure mercury intrusion and nitrogen adsorption indicate that the pore size distributions of the schist and mylonite differ. Compared with the mylonite, the schist has larger reservoir space, more heterogeneity, smaller pore size, larger specific surface area and larger adsorbed gas storage capacity. This paper also studies the formation process of the reservoir and divides it into four stages. Finally, this article discusses in detail the factors controlling the microscopic pore characteristics of metamorphic rock reservoirs in the central paleo-uplift belt; the metamorphic rock protolith is the most important controlling factor.

Combination of Type I and Type II MET Tyrosine Kinase Inhibitors as Therapeutic Approach to Prevent Resistance.

MET-targeted therapies are clinically effective in MET-amplified and MET exon 14 deletion mutant (METex14) non-small cell lung cancers (NSCLCs), but their efficacy is limited by the development of drug resistance. Structurally distinct MET tyrosine kinase inhibitors (TKIs) (type I/II) have been developed or are under clinical evaluation, which may overcome MET-mediated drug resistance mechanisms. In this study, we assess secondary MET mutations likely to emerge in response to treatment with single-agent or combinations of type I/type II MET TKIs using TPR-MET transformed Ba/F3 cell mutagenesis assays. We found that these inhibitors gave rise to distinct secondary MET mutant profiles. However, a combination of type I/II TKI inhibitors (capmatinib and merestinib) yielded no resistant clones in vitro The combination of capmatinib/merestinib was evaluated in vivo and led to a significant reduction in tumor outgrowth compared with either MET inhibitor alone. Our findings demonstrate in vitro and in vivo that a simultaneous treatment with a type I and type II MET TKI may be a clinically viable approach to delay and/or diminish the emergence of on target MET-mediated drug-resistance mutations.

Metaplastic breast carcinoma: a retrospective study of 26 cases.

Metaplastic breast carcinoma is a rare invasive breast cancer. Metaplastic breast carcinoma is mainly characterized by an epithelial or mesenchymal cell population mixed with adenocarcinoma. We collected 26 cases of metaplastic breast carcinoma in the First Affiliated Hospital of Bengbu Medical College from 2008 to 2014. Tumor size, tumor grade, vascular invasion, ER/PR status, histologic classification, and HER2/neu status were assessed for all cases and the literature was reviewed. Clinicopathologic characteristics of patients diagnosed with metaplastic breast carcinomas and its key points of differential diagnosis were discussed. All patients were female, with the median age of 50 years. The mean tumor size was 3.2 cm. 4 subtypes of metaplastic breast carcinomas were documented. Fibromatosis-like metaplastic carcinomas are typically characterized by wavy, intertwined, gentle spindle cells. When the tumor components are almost squamous cell carcinoma components and the primary squamous cell carcinoma of other organs and tissues are excluded, we can diagnose breast squamous cell carcinoma. In spindle cell carcinoma, atypical spindle cells are arranged in many ways and are usually accompanied by inflammatory cell infiltrate. Cancer with interstitial differentiation has mixed malignant epithelial and mesenchymal differentiation, and the mesenchymal components are diverse. Most tumors are triple negative. At present, surgical resection combined with chemotherapy or radiation therapy is the most effective and acceptable method for treating metaplastic breast carcinoma.

Expression of AGGF1 and Twist1 in hepatocellular carcinoma and their correlation with vasculogenic mimicry.

BACKGROUND: The most common reason for hepatocellular carcinoma (HCC) treatment failure is recurrence and metastasis. AGGF1 (a promoting gene of tumor metastasis), vasculogenic mimicry (VM, new blood supply formation in malignant tumors), and Twist1 (an evolutionarily conserved basic helix-loop-helix transcription factor) are all valuable factors for metastasis and prognosis in diverse common human cancers. However, the correlation of AGGF1, Twist1, and VM in HCC is still unclear. In this study, we analyzed the correlations among these factors as well as their correlation with clinicopathologic data and survival in HCC. METHODS: Immunohistochemical (IHC) analysis was used to detect the expression of AGGF1 and Twist1 in 111 archival surgical specimens of human HCC. Furthermore, clinical data were collected. RESULTS: Levels of VM, AGGF1 and Twist1 were significantly higher in HCC tissues than in normal hepatic tissues. Levels of VM, AGGF1, and Twist1 were positively associated with AFP, HBsAg, size, capsular invasion, Child-Pugh classification level, and tumor node metastasis (TNM) stage, and negatively associated with patients' overall survival (OS). In multivariate analysis, high levels of VM, AGGF1, Twist1, AFP, Child-Pugh classification level, as well as TNM stage were independently correlated with lower OS in patients with HCC. CONCLUSION: VM and the expression of AGGF1 and Twist1 may represent promising metastatic and prognostic biomarkers, as well as therapeutic targets for HCC.

Expression of Formin-like 2 and cortactin in gallbladder adenocarcinoma and their clinical significance.

OBJECTIVE: To investigate the expressions of Formin-like 2 (FMNL2) and Cortactin (CTTN) in gallbladder adenocarcinoma (GBAC) and their associations with the clinicopathological characteristics of the patients. METHODS: The expressions of FMNL2 and CTTN were detected with immunohistochemistry (Max Vision) in 105 GBAC tissues and 40 normal gallbladder tissues. RESULTS: The positive expression rates of FMNL2 and CTTN in normal gallbladder tissues were 25% and 20%, different from the positive expression rates of 84.76% and 86.67% in GBAC tissues (P < 0.001). The positive expression rate of FMNL2 and CTTN in GBAC correlated with tumor differentiation, tumor-node-metastasis (TNM), lymph node metastasis (LNM), and distant metastasis. FMNL2 expression was positively correlated with CTTN expression. Kaplan-Meier analysis showed that the overall survival time of patients with positive expressions group of FMNL2 and CTTN was significantly shorter than that of the negative expression group. Cox multivariate analysis showed that TNM, LNM, distant metastasis, and positive expression of FMNL2 and CTTN were independent factors influencing the prognosis of patients with GBAC (P < 0.05). CONCLUSION: The positive expression of FMNL2 and CTTN in GBAC is significantly increased, which may be related to the occurrence and development of GBAC. The combined detection of FMNL2 and CTTN may provide a scientific theoretical basis for the early diagnosis of GBAC, the development of new antitumor drugs, and the search for new targets of biotherapy.

Emotion-behavior decoupling in individuals with schizophrenia, bipolar disorder, and major depressive disorder.

Failure in translating emotional salience into effortful behavior is thought to be a core feature of anhedonia and avolition in individuals with schizophrenia (SCZ), but little is known about emotion-behavior coupling in individuals with bipolar disorder (BD) and major depressive disorder (MDD). In this study, we compared emotion-behavior correspondence in participants with SCZ, BD, and MDD. Forty-two participants with SCZ, 44 participants with MDD, 43 participants with BD, and 43 healthy controls were recruited. A computerized anticipatory and consummatory pleasure task was used to evaluate emotion-behavior correspondence. Clinical ratings of negative symptoms and self-report anhedonia questionnaires were also administered. We found that participants with SCZ, MDD, and BD exhibited different levels of negative symptoms and self-reported anhedonia, as well as emotion-behavior decoupling. In SCZ participants, both desirable and undesirable images elicited lower correspondence between self-reported liking and behavior. In MDD and BD participants, undesirable images elicited lower emotion-behavior correspondence under both direct stimulus presentation and representation conditions, whereas deficits in emotion-behavior coupling under desirable conditions were only observed when stimuli were present. Taken together, emotion-behavior decoupling showed both common and unique patterns in participants with SCZ, MDD, and BD, and showed some associations with negative symptoms and anhedonia across the combined clinical sample. This finding may be helpful for early identification and the development of novel interventions for different psychiatric diagnoses. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

A Complex of U1 snRNP with Cleavage and Polyadenylation Factors Controls Telescripting, Regulating mRNA Transcription in Human Cells.

Full-length transcription in the majority of human genes depends on U1 snRNP (U1) to co-transcriptionally suppress transcription-terminating premature 3' end cleavage and polyadenylation (PCPA) from cryptic polyadenylation signals (PASs) in introns. However, the mechanism of this U1 activity, termed telescripting, is unknown. Here, we captured a complex, comprising U1 and CPA factors (U1-CPAFs), that binds intronic PASs and suppresses PCPA. U1-CPAFs are distinct from U1-spliceosomal complexes; they include CPA's three main subunits, CFIm, CPSF, and CstF; lack essential splicing factors; and associate with transcription elongation and mRNA export complexes. Telescripting requires U1:pre-mRNA base-pairing, which can be disrupted by U1 antisense oligonucleotide (U1 AMO), triggering PCPA. U1 AMO remodels U1-CPAFs, revealing changes, including recruitment of CPA-stimulating factors, that explain U1-CPAFs' switch from repressive to activated states. Our findings outline this U1 telescripting mechanism and demonstrate U1's unique role as central regulator of pre-mRNA processing and transcription.

Multifocal perivascular epithelioid cell tumor of the uterus: report of one case and literature review.

BACKGROUND: The tumor with perivascular epithelioid cells (PEComa) is a rare mesenchymal tumor originating from a perivascular epithelioid cell line. The uterus is the most common location of PEComa, but multifocal lesions are rare. This study aimed to analyze the clinicopathologic and histochemical characteristics of uterine PEComa. METHODS: 1 case of uterine PEComa was detected by H&E staining and immunohistochemical SP method. RESULTS: The 41-year-old female patient was admitted to the hospital due to gynecologic ultrasonography which showed a substantial heterogeneous mass in the pelvic cavity. According to the microscopic features and immunohistochemical markers, the tumor was diagnosed as multifocal tumors with perivascular epithelioid cells, specifically located on the serous surface of the uterus and below the right appendix. The immunophenotype of the patient was positive for Vimentin, HMB45, TFE-3 and WT-1, but negative for SMA, S-100, CD10, CK, EMA, CD117, CD31 and Melan-A. CONCLUSION: PEComa is a rare mesenchymal tumor with benign manifestations. Pathological diagnosis should be combined with morphology and immunophenotype. The characteristic immunomarkers are HMB45, Melan-A and SMA. The understanding of clinical manifestations and pathologic features can improve the diagnosis and prevention of this type of tumor in female patients.

Ectopic thymoma: report of 2 cases and review of the literature.

In this report, we present two cases of ectopic thymoma, aiming to explore the clinicopathologic features, diagnosis, and differential diagnosis of ectopic thymoma. Case 1 was a female 56-years-old. For 6 months' time, there was no obvious cause of cough, expectoration, chest tightness, or asthma with chest pain. PET-CT showed a right middle lung and lower lung mass with increased FDG metabolism. Postoperative pathology was diagnosed as right middle and lower lung ectopic thymoma, type B2, invading the chest wall. Case 2 was a male of 54-years-old. By physical examination the right chest cavity had a mass present for 1 week and he was admitted to hospital. Postoperative pathology was diagnosed as right thoracic ectopic thymoma, type AB. No recurrence has been found to in the follow-up of these two patients. In conclusion, ectopic thymoma occurs outside the anterior mediastinum. It is rare, the clinical symptoms are not typical, and pre-operative diagnosis is difficult. It is easily misdiagnosed as other diseases. Surgical treatment is the best method. According to the pathologic type and invasion of the tumor, radiotherapy may be considered.

Clinicopathologic features of epithelioid sarcoma: report of seventeen cases and review of literature.

Epithelioid sarcoma (ES) is a rare malignant soft tissue tumor, which is characterized by nodular aggregates of epithelioid cells and immunoreactivity of cytokeratin (CK) as well as epithelial membrane antigen (EMA) and often with CD34. It can be divided into proximal and distal subtypes. Classic ES has a microscopic nodular appearance that is composed of large polygonal epithelioid cells combined with central necrosis, and presents as a subcutaneous or deep dermal mass in the distal extremities of young adults. The proximal variant preferentially occurs in proximal limbs and limb girdles and the midline of the trunk, and is composed of more atypical cells with variable rhabdoid morphology. In this study we investigated the clinicopathologic features of 17 patients diagnosed with ES. In addition, we reviewed relevant literature and discussed some diagnostic and differential diagnostic points of this disease.

U1 snRNP telescripting regulates a size-function-stratified human genome.

U1 snRNP (U1) functions in splicing introns and telescripting, which suppresses premature cleavage and polyadenylation (PCPA). Using U1 inhibition in human cells, we show that U1 telescripting is selectively required for sustaining long-distance transcription elongation in introns of large genes (median 39 kb). Evidence of widespread PCPA in the same locations in normal tissues reveals that large genes incur natural transcription attrition. Underscoring the importance of U1 telescripting as a gene-size-based mRNA-regulation mechanism, small genes were not sensitive to PCPA, and the spliced-mRNA productivity of ∼1,000 small genes (median 6.8 kb) increased upon U1 inhibition. Notably, these small, upregulated genes were enriched in functions related to acute stimuli and cell-survival response, whereas genes subject to PCPA were enriched in cell-cycle progression and developmental functions. This gene size-function polarization increased in metazoan evolution by enormous intron expansion. We propose that telescripting adds an overarching layer of regulation to size-function-stratified genomes, leveraged by selective intron expansion to rapidly shift gene expression priorities.

Experimental demonstration of building and operating QoS-aware survivable vSD-EONs with transparent resiliency.

Software-defined elastic optical networks (SD-EONs) provide operators more flexibility to customize their optical infrastructures dynamically. By leveraging infrastructure-as-a-service (IaaS), virtual SD-EONs (vSD-EONs) can be realized to further enhance the adaptivity of SD-EONs and shorten the time-to-market of new services. In this paper, we design and demonstrate the building and operating of quality-of-service (QoS) aware survivable vSD-EONs that are equipped with transparent data plane (DP) resiliency. Specifically, when slicing a vSD-EON, our network hypervisor (NHV) chooses to use "1:1" virtual link (VL) protection or on-demand VL remapping as the DP restoration scheme, according to the service-level agreement (SLA) between the vSD-EON's operator and the infrastructure provider (InP). Then, during an actual substrate link (SL) failure, the NHV realizes automatic DP restoration that is transparent to the controllers of vSD-EONs. We build a network testbed to demonstrate the creation of QoS-aware survivable vSD-EONs, the activation of lightpaths in the vSD-EONs to support upper-layer applications, and the automatic and simultaneous QoS-aware DP restorations during an SL failure. The experimental results indicate that our vSD-EON slicing system can build QoS-aware survivable vSD-EONs on-demand, operate them to set up lightpaths for carrying real application traffic, and facilitate differentiated DP restorations during SL failures to recover the vSD-EONs' services according to their SLAs.

THZ1 Reveals Roles for Cdk7 in Co-transcriptional Capping and Pausing.

The Cdk7 subunit of TFIIH phosphorylates RNA polymerase II (Pol II) during initiation, and, while recent studies show that inhibition of human Cdk7 negatively influences transcription, the mechanisms involved are unclear. Using in vitro transcription with nuclear extract, we demonstrate that THZ1, a covalent Cdk7 inhibitor, causes defects in Pol II phosphorylation, co-transcriptional capping, promoter proximal pausing, and productive elongation. THZ1 does not affect initiation but blocks essentially all Pol II large subunit C-terminal domain (CTD) phosphorylation. We found that guanylylation of nascent RNAs is length dependent and modulated by a THZ1-sensitive factor present in nuclear extract. THZ1 impacts pausing through a capping-independent block of DSIF and NELF loading. The P-TEFb-dependent transition into productive elongation was also inhibited by THZ1, likely due to loss of DSIF. Capping and pausing were also reduced in THZ1-treated cells. Our results provide mechanistic insights into THZ1 action and how Cdk7 broadly influences transcription and capping.